WO2012092665A1

WO2012092665A1 - Method for facilitating tissue transplantation

Info

Publication number: WO2012092665A1
Application number: PCT/CA2012/000004
Authority: WO
Inventors: Geoffrey W. Hoffmann
Original assignee: Network Immunology Inc.
Priority date: 2011-01-04
Filing date: 2012-01-04
Publication date: 2012-07-12
Also published as: WO2012092664A1; WO2012092663A1

Abstract

The present disclosure provides methods for facilitating organ transplantation using anti-anti- donor IgG. The methods include a method for producing affinity purified anti-anti-donor antibodies. The methods further include methods for the induction of transplantation tolerance between an organ donor and an organ recipient, and a method for the induction of reciprocal transplantation tolerance between two vertebrates, such that each can potentially be an organ donor for the other.

Description

METHOD FOR FACILITATING TISSUE TRANSPLANTATION

FIELD

[0001] This disclosure relates at least in part to methods of facilitating tissue transplantation. The present disclosure relates at least in part to uses of anti-anti-donor antibodies.

Embodiments of the present methods relate to using anti-anti-donor IgG antibodies to specifically suppress the immune response of a recipient to donor tissue. The present disclosure further relates to compositions, uses, methods, kits, antibodies, and the like.

BACKGROUND

[0002] Although transplantation of organs, tissues or cells from one genetically distinct person (donor) to another (recipient) is relatively commonplace, a shortage of acceptable donors and immunologic rejection of the donated tissue by the recipient remain major hindrances. It is understood that the rejection of a donor's tissue involves both cellular and humoral mechanisms, mediated respectively by T cells and antibodies. The recipient's immune system especially targets histocompatibility antigens on the transplanted cells that are not seen as "self but rather as foreign entities. Except for cases of organ donation between immunologically identical individuals or the special instance of transplantation in individuals with severe combined immunodeficiency disease, the donor's histocompatibility antigens will not completely match the recipient's histocompatibility antigens, and the recipient's immune system will almost certainly react to the incompatible donor's organs, tissues or cells.

[0003] With respect to immunologically-mediated rejection, the most potent of the histocompatibility antigens are the major histocompatibility complex (MHC) antigens known in humans as the human leukocyte antigens (HLAs) which are present on virtually all of the nucleated cells of the human body. The MHC class I antigens include the HLA-A, HLA-B and HLA-C antigens. Since each person receives genes encoding one set of these antigens from each parent, human cells typically express six of these major HLA class I antigens. Organ donors and recipients can also differ in their MHC class II antigens (HLA class II antigens). In addition to the major histocompatibility antigens, there are several minor histocompatibility antigens and other antigens that may limit transplantation success including the ABO and Rh systems.

[0004] When tissue or cells are transplanted, it is desirable to match, to the maximum extent possible, the histocompatibility antigens of the donor and the recipient. The best immunologic match between donor and recipient is between identical twins, since they share the same major HLA antigens and the same minor histocompatibility antigens; therefore, the recipient identical twin will immunologically tolerate the identical twin donor's organs, tissue or cells.

[0005] More commonly, however, the donor and recipient are not genetically identical resulting in some degree of rejection to the transplanted tissue. To minimize this rejection and permit survival of the engrafted tissue, efforts are routinely made to find the best match between donor and recipient. Even in the best case scenario, there is still a high probability that the minor histocompatibility antigens differ (and likely the major HLA antigens as well), and the donor and recipient will almost certainly be sufficiently distinct in terms of cellular antigens, which results in some degree of graft rejection. In some circumstances, a negative cross-match indicates a recipient has antibodies against the red blood cells of the donor, in which case the donor cannot donate tissue or cells to the recipient without the recipient's immune system responding. Due partly to these negative cross-matches, only a small percentage of available donor-organs or donor-tissues are actually suitable for any given potential recipient.

[0006] If transplantation is carried out, the adverse reactions following transplantation of an organ or tissue from one genetically distinct individual to another can be profoundly dangerous. The primary adverse reaction is immunologic rejection of the transplanted organ or tissue. If the organ is life-sustaining, such as a heart, liver or lung, the destruction of that organ may lead directly to the death of the patient. In other circumstances, such as rejection of insulin-producing pancreatic islet cells or kidneys, the quality of life of the recipient may be devastated by the tissue rejection.

[0007] In order to prevent or limit the rejection, various agents and therapies have been used including: (1) corticosteroids, such as prednisone; (2) cytotoxic drugs, such as azathioprine and cyclophosphamide; (3) x-ray irradiation therapy; (4) anti -lymphocyte and anti-thymocyte globulins; (5) cyclosporine; and (6) monoclonal antibodies, such as OKT3, which reacts specifically with the CD3 antigen-recognition structure of human T cells and blocks the T cell effector function involved in allograft rejection. These agents and therapies are all administered post-transplant and introduce their own undesirable side effects. For example, immunosuppressive drugs, such as prednisone and cyclosporine, are globally

immunosuppressive, which greatly increases the susceptibility of the recipient to serious infections and also increases the susceptibility of the recipients to opportunistic infections, against which normal individuals have strong defenses. High doses of corticosteroids may also cause cataracts, precipitate diabetes mellitus and hypertension, and/or cause

demineralization of supporting bones, leading to arthritis or osteoporosis. Cyclosporine may cause hypertension, tremors, anorexia and elevated low-density lipoprotein levels. It also has major toxic effects on the kidney, which may lead to decreased renal function. Cytotoxic agents may cause anemia and thrombocytopenia and sometimes hepatitis. The anti- lymphocyte globulins may cause fever, hypotension, diarrhea, or sterile meningitis. O T3 may cause chills and fever, nausea, vomiting, diarrhea, rash, headache, photophobia and occasional episodes of life-threatening acute pulmonary edema.

[0008] In addition to the issues of transplant rejection, the need for chronic immune suppression following transplantation and the resulting adverse effects of post-transplant treatment, there is a marked shortage of human organ and tissue donors compared to the number of patients requiring a transplant.

[0009] Xenografts, herein defined as transplants from another species, could potentially resolve the shortage of transplantable organs and tissues. Xenografts have been used in the past for short term life support when a recipient urgently requires a transplant and no suitable donor is available. Such uses, however, have only been temporary measures to provide additional time to locate a suitable human donor. The potential use of xenografts as long-term grafts for human recipients is limited by the same major issues that affect allografts; i.e., rejection of the donor graft and the adverse effects of anti-rejection treatments. The problem of rejection is even heightened with xenografts as the risk of rejection of xenografts is considered to be even greater than for allografts.

[0010] Reducing the risk of rejection of donated tissue, xenograft and/or allograft, especially with few excessive adverse effects is desirable. For example, an immunologically-specific immune system suppressant which has few or no side-effects would be valuable.

[0011] Previous methods aimed at modulating a recipient's response to a donor graft have been disclosed. See, for example, US Patent No. 6,060,049, US Patent No. 5,560,911, US Patent No. 5,728,812, International Patent Application No. WO 84/02848, US Patent Application No. 2008/0127357 and US Patent Application No. 2001/0053362).

SUMMARY

[0012] In part, the present disclosure describes anti-anti-MHC antibodies. [0013] In part, the present disclosure describes a use of anti-anti-MHC antibodies in reducing a recipient's immune response to donated tissue. The present use comprises introducing anti- anti-(donor MHC) antibodies to the recipient's immune system.

[0014] In part, the present disclosure describes compositions comprising anti-anti-MHC antibodies.

[0015] In part, the present disclosure describes human anti-anti-MHC antibodies.

[0016] In part, the disclosure describes fragments of human anti-anti-MHC antibodies.

[0017] In part, the present disclosure describes methods of producing human anti-anti-MHC antibodies.

[0018] In part, the present disclosure describes a use of anti-anti-MHC antibodies to facilitate tissue donation between appropriate pairs of vertebrate organisms. For example, organ donation between spouses, other relatives, partners, or other individuals. Further, the present disclosure describes a means for preparing a vertebrate organism or organisms for possible tissue donation to another vertebrate, for example in situations where married or common-law spouses wish to donate organs to their spouse, is also desired. Each member of a couple could benefit from being made immunologically tolerant to the tissue of the other. Then each member would be available as an organ donor for the other, should the need arise. This would facilitate the use of living donors for transplantations.

[0019] In part, the present disclosure describes a use of anti-anti-MHC antibodies in making each member of a pair of vertebrate organisms ("partners") immunologically tolerant to the tissue and organs of the other.

[0020] In part, the present disclosure describes a method of supplying anti-anti-(donor MHC) antibodies suitable for administration to an organ recipient, the method comprising: a. receiving input parameters, said parameters comprising donor lymphocytes; b. obtaining, based on the input parameters, an appropriate anti-anti-(donor MHC) antibodies for facilitating the transplantation of tissue from said donor to a recipient; and c. distributing said anti-anti-(donor MHC) antibodies to the delivery location. [0021] As used herein, the term "immune response" means the production of antibodies and/or the induction of cell mediated immunity specific for an antigen, including especially the production of antibodies or the induction of cell mediated immunity specific for transplantation antigens.

[0022] As used herein, the term "facilitating transplantation" means reducing the risk of rejection of donated tissue by a recipient. For example, when the donated tissue is an organ the term will refer to reducing the chance of rejection of the organ by the recipient and a consequent improvement in the chances of the transplantation being successful. The facilitation process can include inducing transplantation tolerance by the administration of anti-anti-donor antibodies in non-immunogenic form to a prospective donor recipient.This may be together with the application of a prospective donor skin graft. This process can induce transplantation tolerance in the recipient with respect to donor tissue such as donor organs, and organ transplantation can be attempted as needed.

[0023] As used herein, the term "idiotype" means the unique set of antigenic determinants (or epitopes) of the V region of an antibody, lymphocyte receptor or specific T cell factor, wherein such idiotype can potentially induce the formation of anti-idiotypic antibodies.

[0024] As used herein, the term "anti-idiotype" means the V region of an antibody, lymphocyte receptor or specific T cell factor that is complementary to the V region of the respective idiotype.

[0025] As used herein, an animal P that has made an anti-Q immune response, where P and Q are vertebrates, is "conversely alloimmune" to an animal Q that has made an anti-P immune response.

[0026] As used herein, the term "converse alloimmune serum" for a P anti-Q serum is a Q anti-P antiserum.

[0027] As used herein, the term "anti-anti-self antibody" in an alloimmune serum is an antibody that binds to an idiotype in the converse alloimmune serum (see Figure 1). In the case of complementary alloimmune sera, as shown for example in Figure 1, anti-anti-P antibodies in a P anti-Q serum can bind to anti-P and anti-anti-anti-P antibodies in a Q anti-P serum. Anti-anti-self antibodies, for example anti-anti-P in Figure 1, are predominantly anti- anti-(self MHC), because of the strong role that MHC antigens play in alloimmunity, but other self antigens also play a role in the selection of anti-anti-self antibodies, including but not limited to minor histocompatibility antigens.

[0028] As used herein, the term "anti-anti-MHC antibody" means an antibody in an alloimmune serum that binds to an anti-MHC and/or an anti-anti-anti-MHC antibody in the converse alloimmune serum (see Figure 1). Anti-anti-MHC antibodies are distinct from antiidiotypic antibodies that are selected and produced by purifying an idiotype bearing antibody and immunizing a vertebrate with that idiotype. In the context of a P anti-Q immune response and a Q anti-P immune response, where P and Q are vertebrates, anti-anti-P antibodies in a P anti-Q serum bind to anti-P and anti-anti-anti-P antibodies in a Q anti-P serum.

[0029] As used herein, the term "organism" or "subject" refers to any vertebrate organism.

[0030] As used herein, the term "anti-anti-graft antibody" is synonymous with anti-anti-donor antibody.

[0031] As used herein, the term "anti-anti-anti-MHC antibody" in the context of a P anti-Q immune response, where P and Q are vertebrates, means an antibody present in an P anti-Q serum, or a monoclonal antibody, that binds to the V regions of the anti-anti-Q antibodies present in a Q anti-P serum, but not to vertebrate Q MHC antigens; see Figure 1. The anti- anti-anti-MHC antibodies in this case are anti-anti-anti-Q antibodies. Hybridomas that produce monoclonal anti-anti-anti-donor antibodies can be selected using alloimmune animals on the basis of their V regions having complementarity to anti-anti-donor antibodies without also binding to donor MHC antigens. These anti-anti-anti-MHC antibodies are believed to bind in ELISA assays to HIV antigens, and it is believed that hybridomas that make monoclonal anti-anti-anti-MHC antibodies can be selected using alloimmune animals and selecting hybridomas with V regions that bind to HIV antigens.

[0032] As used herein, the term "monoclonal anti-anti-anti-graft antibody" is synonymous with monoclonal anti-anti-anti-(donor MHC) antibody.

[0033] As used herein, "HIV" is the human immunodeficiency virus, including especially the HIV-1 human immunodeficiency virus.

[0034] As used herein, the term "monoclonal donor-specific anti-HIV antibodies" means monoclonal antibodies that are obtained by multiply immunizing a vertebrate with donor lymphocytes and selecting hybridomas with V regions that bind to HIV antigens. [0035] As used herein, "non-immunogenic" means delivery in a manner that does not induce significant production of antibodies that bind to the antibodies being administered. For example, the delievery may be without an adjuvant, via a non-immunogenic route, and/or in non-immunogenic amounts.

[0036] As used herein, the term "anti-anti-(donor MHC) antibody" means an anti-idiotype antibody that is present in an alloimmune serum and that is directed against the idiotypes of anti-(donor MHC) antibodies and anti-(donor MHC) T cell receptors that are present in the converse antiserum, and can recognize and interact with anti-(donor MHC) antibodies and anti-(donor MHC) T cell receptors that are present in the converse antiserum.

[0037] As used herein, the term "recipient" refers to a vertebrate organism which receives tissue from a genetically distinct organism.

[0038] As used herein, the term "donor" refers to a vertebrate organism from which tissue is removed or otherwise derived by, for example, tissue culturing techniques, and introduced into the recipient organism. The donor may be of the same (allograft) or different (xenograft) species.

[0039] As used herein, the term "catalyst animal" refers to a vertebrate organism that provides tissue, preferably lymphocytes, that is used for the immunization of a potential organ donor vertebrate, such that the donor makes an immune response that includes the production of anti-anti-donor antibodies. For the case of a given prospective organ donor and a given prospective organ recipient, a catalyst animal may be a third party vertebrate animal.

[0040] As used herein, the term "tissue" means one or more nucleated cells. Frequently, the tissue will be from an organ such as, for example, skin, heart, lung, kidney, liver, spleen, thymus, lymph node, blood, bone marrow, pancreas, intestine, gall bladder, prostate, ovary, muscle, limbs, or the like. The tissue may be a whole or partial organ.

[0041] This summary does not necessarily describe the entire scope of the present invention. Other aspects, features and advantages of the invention will be apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 shows a system by which anti-, anti-anti-, and anti-anti-anti- antibodies are defined and are believed to be present in alloimmune or xenoimmune vertebrates. A vertebrate "P" with MHC antigens P that is alloimmune or made alloimmune to a vertebrate "Q" with MHC antigens Q is believed to make anti-Q, anti-anti-P and anti-anti-anti-Q antibodies. If the vertebrate "Q" is alloimmune or is made alloimmune to the vertebrate "P", "Q" is believed to make anti-P, anti-anti-Q and anti-anti-anti-P antibodies. The anti-anti-Q antibodies in the Q anti-P serum are believed to have specificity for anti-Q and anti-anti-anti- Q antibodies in the P anti-Q serum.

[0043] Figure 2 illustrates the IJ phenomenon in the context of the symmetrical immune network theory.

[0044] Figure 3 shows a possible mechanism for an anti-anti-(MHC class II) monoclonal antibody in immunogenic form being a vaccine for the prevention of infection with HIV. Alpha (a) is an abbreviation for "anti-". Helper T cells are selected to have some affinity for MHC class II antigens. The helper T cells are coselected with suppressor T cells that are anti- anti-(MHC class II), or more succinctly "anti-anti-self '. Since HIV preferentially infects HIV- specific helper T cells, HIV is also coselected with the helper T cells, and HIV has an anti- anti-(MHC class II) shape. The anti-anti-(MHC class II) monoclonal antibody selects anti- anti-anti-(MHC class II) lymphocytes that are anti-HIV. This anti-HIV response eliminates HIV. Both the anti-anti-anti-P antibodies and the anti-anti-anti-Q antibodies of Figure 1 are believed to bind to proteins of HIV.

[0045] Figure 4 shows a possible mechanism for the induction of transplantation tolerance using anti-anti-(graft MHC) antibodies. Alpha (a) is an abbreviation for "anti-" and "tab" means specific T cell factor. The single arrows denote stimulation. The double arrows denote arming, meaning tabs binding to the surface of non-specific accessory cells (A cells) including macrophages and monocytes. Evans et al. (1972) J. Exp. Med., 136, 1318. The tabs on the surface of the A cells form an immunogenic array. Anti-anti-graft antibodies (aagraft IgG) stimulate agraft and aaagraft T cells. The agraft T cells are also stimulated by the graft. The agraft and aaagraft T cells secrete agraft and aaagraft tabs respectively. The agraft and aaagraft tabs bind to the surface of A cells. The agraft and aaagraft tabs on the A cells stimulate aagraft T cells. The aagraft T cells secrete aagraft tabs that also bind to the surface of A cells. Thus the A cells become armed with a mixture of agraft, aagraft and aaagraft tabs. The armed A cell stimulates the proliferation of agraft, aagraft and aaagraft T cells. In the context of the symmetrical immune network theory, the resulting state of the system with elevated levels of agraft, aagraft and aaagraft T cells is believed to be a specifically suppressed state with regard to making an immune response to the graft.

[0046] Figure 5 shows a method for the induction of transplantation tolerance between two vertebrates P and Q using the immune system of a third party "catalyst" vertebrate C in the production of anti-anti-self antibodies. P and Q are both immunized with tissue of C preferably including lymphocytes, such that the immune response of the immunized vertebrate includes the production of anti-anti-self antibodies. Serum of P and Q is taken and is absorbed using tissue of C, leaving anti-anti-P and anti-anti-Q antibodies in the absorbed P anti-Q and absorbed Q anti-P sera respectively. P receives a Q skin graft together with anti- anti-Q antibodies and Q receives a P skin graft together with anti-anti-P antibodies. When the skin grafts are stably accepted, P and Q are each ready to receive an organ transplant from the other, should the need arise.

DETAILED DESCRIPTION

[0047] In part, the present disclosure describes methods of reducing the risk of the rejection of tissue transplanted into a recipient animal from a donor animal. In an embodiment, the present disclosure provides a method of producing anti-idiotypic antibodies against antigen receptors on the surface of a recipient's lymphocytes and the use of such anti-idiotypic antibodies in preventing transplant rejection by a recipient by inducing a state of the recipient's immune system that is suppressed with regard to responding immunologically against the transplanted organ. The present disclosure further relates to compositions, uses, kits, and the like.

[0048] An embodiment of the present method involves the immune systems of a recipient animal "R", a donor animal "D" and a catalyst animal "C", wherein the recipient animal and the donor animal are preferably, but not necessarily, of the same species. The method may involve the production of anti-anti-(donor MHC) antibodies for administration to the recipient animal.

[0049] One method comprises obtaining cells from C. Preferably, the cells comprise lymphocytes. The cells preferably include cells with receptors on their surface with anti- (donor MHC) specificity. For safety the cells are preferably made non- viable by, for example, gamma irradiation or other suitable method. [0050] The said method may further comprise exposing cells, for example T cells and/or B cells, of the donor D immune system to the selection of cells from C such that an immune response of D is induced against the said selection of cells from C. The method may further comprise exposing cells, for example T cells and/or B cells, of the immune system of the catalyst C to cells from the donor D such that an immune response is induced in the catalyst against the said cells from D. These exposures can be historical, such that D is alloimmune or is made alloimmune to C and C is alloimmune or is made alloimmune to D. The two immune responses may include making anti-(foreign MHC), anti-anti-(self MHC) and anti-anti-anti- (foreign MHC) as shown in Figure 1.

[0051] Figure 1 shows the antibodies that are produced when two animals P and Q are each immunized with lymphocytes of the other. The anti-anti-P antibodies in a P anti-Q serum bind specifically to anti-P and anti-anti-anti-P antibodies in a Q anti-P serum. The anti-anti-self antibodies are predominantly anti-anti-(self MHC), because of the strong role that MHC antigens play in alloimmunity. The present anti-anti-(self MHC) antibodies can be obtained on the basis of having complementarity to anti -(foreign MHC) and/or anti-anti-anti-(foreign MHC) antibodies in the converse antiserum.

[0052] As shown in Figure 1 , the serum of an animal P that has been immunized with Q lymphocytes contains anti-Q, anti-anti-P, and anti-anti-anti-Q antibodies, while the serum of an animal Q that has been immunized with lymphocytes of an animal P contains anti-P, anti- anti-Q, and anti-anti-anti-P antibodies. In the context of the symmetrical immune network theory, the anti-anti-anti-P antibodies and anti-anti-anti-Q antibodies are called anti-IJ^p and anti-IJ^Q antibodies in mice. The diagonal lines in this diagram indicate that all of the specific antibodies induced in the P anti-Q serum have complementarity to antibodies in the Q anti-P serum. Hence as used herein, the term "anti-anti-anti-MHC antibody" in the context of an P anti-Q immune response, where P and Q are vertebrates, means an anti-anti-anti-(Q MHC) antibody, or a monoclonal antibody, that binds to the V regions of anti-anti-(Q MHC) antibodies present in a Q anti-P serum, but not to vertebrate Q MHC antigens.

[0053] As used herein, the term "co-selection" means the mutual positive selection of individual members from within two diverse populations, such that selection of members within each population is dependent on interaction with (recognition of) one or more members within the other population (Hoffmann, G. W. 1994. Immunol. Cell Biol., 72:338). [0054] While not wishing to be bound by theory, the present method is believed to work based on the symmetrical immune network theory, according to which the variable regions (the "V regions") of antibodies, specific T cell factors, and specific lymphocyte receptors recognize each other and that such recognition is a key element in the regulation of the immune system. The V regions of antibodies, lymphocyte receptors and specific T cell factors each have a set of antigenic determinants (or epitopes) that characterize each type of antibody, receptor and specific T cell factor. These sets of antigenic determinants are referred to as idiotypes and function in their own right as antigenic stimuli, which can induce the formation of anti-idiotypic antibodies. An anti-idiotype is a set of antigenic determinants complementary to its respective idiotypes. The interactions between idiotypes and anti-idiotypes and the interaction between idiotypic receptors and anti-idiotypic receptors is thought to be a major factor in regulating a specific immune response (see, for example, Wigzell, H. and Binz, H. 1980. Progress in Immunology IV, eds. Fougereau, M. and Dausset, J. Academic Press, N.Y., p. 94-103; Infante, et al. 1982. J. Exp. Med. 155: 1 100; Bona, C. and Paul, E. 1980.

Regulatory T Lymphocytes, eds., Pernis, B. and Vogel, H.J. Academic Press, N.Y., p. 292). The interactions between idiotypes and anti-idiotypes is thought to be symmetrical. The symmetrical interactions are thought to include symmetrical stimulation, inhibition, and elimination interactions. The symmetrical immune network theory is described in "Immune Network Theory" by Hoffmann, G. W., published at online at

www.networkimmunologyinc.com. However, for a variety of reasons symmetrical immune network theory has been largely discounted by the scientific community and the vast majority of immunologists are not further pursuing or researching the theory. One issue with the theory is that it is based on the presumed existence of molecules called specific T cell factors, or "tabs", which are integral to the symmetrical immune network theory, but are not part of the reigning paradigm of adaptive immunity in the year 2010. A second cause for the

unpopularity of the symmetrical immune network theory is known as the IJ paradox. Tabs were shown experimentally to express IJ determinants, and IJ was clearly mapped in mice to within the MHC, but no gene for IJ could be found there. This was the IJ paradox. The IJ paradox led to the widespread conclusions that "IJ does not exist" and "suppressor tabs do not exist". Since tabs are important in the symmetrical immune network theory, it has been widely concluded that the symmetrical immune network theory is wrong. [0055] In spite of the technical prejudice that exists against immune network theory , the present disclosure describes anti-anti-MHC antibodies and uses thereof in technologies that are based on immune network theory.

[0056] The present disclosure comprises methods for facilitating organ transplantation from a donor to a recipient. These methods involve the use of anti-anti-donor antibodies. This disclosure describes methods for obtaining anti-anti-donor antibodies and/or fragments of anti-anti-donor antibodies, where the donor is a prospective donor of an organ. These antibodies may be produced in any suitable method such methods being well known in the art. Preferred methods of producing anti-anti-donor antibodies are described below in Examples 1 and 2.

[0057] The present use of anti-anti-donor antibodies may comprise administering the antibodies to the recipient in non-immunogenic form. The dose of anti-anti-donor antibodies may be determined by one skilled in the art. Preferably, the recipient is given anti-anti-donor antibodies intravenously or intra-peritoneal without an adjuvant, in amounts preferably between about 10 ng and about 10 μg of anti-anti-donor antibody per kilogram weight of the recipient per dose, such as about 1 μg of anti-anti-donor antibody per kilogram of the recipient per dose.

[0058] In an embodiment, donor serum comprising anti-anti-donor antibodies is administered to the recipient, which administration comprises: (i) obtaining serum or purified IgG antibodies from an immunized donor; (ii) adsorbing the donor's serum or purified IgG antibodies using recipient tissue in order to remove any anti-recipient antibodies; and (iii) administering the resulting serum or purified IgG antibodies containing anti-anti-donor activity to the recipient to facilitate acceptance of the donor's graft.

[0059] Figure 4 shows how a possible mechanism for how anti-anti-graft antibodies, which are also known as "anti-anti-donor antibodies", are believed to facilitate the induction of transplantation tolerance. The anti-anti-graft antibodies, when administered to the recipient, cause a stimulatory immune response by the T cells of the recipient. The anti-anti-graft antibodies stimulate anti-anti-anti-graft T cells and anti-graft T cells, which causes the secretion of specific T cell factors. These T cell factors are protein molecules that are postulated to be monovalent (i.e., having only one V region). The V regions of specific T cell factors mediate the T cell factors' specificity. Since T cell factors are monovalent, T cell factors in soluble form cannot cross-link complementary receptors; however, such soluble T cell factors can be stimulatory when presented on the surface of non-specific accessory cells ("A cells") including macrophages.

[0060] The T cell factors that are secreted by the anti-anti-anti-graft T cells and anti-graft T cells have anti-anti-anti-graft specificity and anti-graft specificity respectively. These T cell factors of a given specificity are adsorbed by and presented on the surface of macrophages. The surface of the macrophage is a highly immunogenic surface, and the presence of the specific T cell factors on the surface of macrophages stimulate T cells bearing receptors that are complementary to the T cell factors on the macrophage surface. While not wishing to be bound by theory, it is believed that the anti-anti-anti-graft T cell factors and anti-graft T cell factors specifically stimulate anti-anti-graft T cells. These anti-anti-graft T cells secrete anti- anti-graft specific T cell factors, which in turn are presented on the surface of macrophages, resulting in the proliferation of anti-graft T cells and anti-anti-anti-graft T cells. As a result of the symmetric stimulation of T cells, the macrophages of the recipient become armed with a mixture of anti-graft, anti-anti-graft and anti-anti-anti-graft T cell factors. Consequently, the immune system of the recipient goes into a state in which there are elevated levels of anti- graft, anti-anti-graft and anti-anti-anti-graft T cells, and their mutual stimulation leads to a significant level of these cells and their corresponding antigen-specific T cell factors. In the context of the symmetrical immune network theory, this is thought to be a specifically suppressed state for the recipient especially with regard to the MHC antigens of the organ donor. The recipient's immune system is therefore selectively suppressed with respect to any immunity against the antigens of the donor, while still leaving the remainder of the immune system intact and not injuring other important organs, tissues or cells.

[0061] The present disclosure can also involve a donor animal that is a different species from the recipient animal, i.e., a xenogeneic transplantation. Many species could potentially be used as donor animals and different animals offer advantages for select uses. Preferably, donor animals are of the class Mammalia. Of the class Mammalia, five orders are particularly suitable for human recipients: primates, artiodactyls, carnivores, rodents, and lagamorphs.

[0062] In an embodiment a potential organ recipient receives anti-anti-donor antibodies preferably substantially concurrent with a skin graft. Additional doses may be given at intervals thereafter. The anti-anti-donor antibodies can also be given prior to the time of a skin graft. When the skin graft is stably accepted, the potential organ recipient is more transplantation tolerant with respect to the tissue of the potential organ donor, and can receive an organ transplant as needed.

[0063] The anti-anti-donor antibodies can also be given at the time of the organ transplant. Additional doses may be given at intervals thereafter. It may be desirable to establish transplantation tolerance with a skin graft as described hereinabove before transplanting the organ.

[0064] In an embodiment affinity purified anti-anti-donor antibodies are obtained using monoclonal anti-anti-anti-donor antibodies. A prospective organ donor is immunized with tissue, preferably comprising lymphocytes, of a catalyst vertebrate C, and makes anti-C, anti- anti-donor and anti-anti-anti-C antibodies. A vertebrate animal C is immunized with donor lymphocytes and makes anti-donor, anti-anti-C and anti-anti-anti-donor antibodies. B lymphocytes from the vertebrate C are used to make hybridomas. Hybridomas are selected that have V regions that bind to HIV antigens. These hybridomas are believed to have anti- anti-anti-donor specificity, and are used to produce monoclonal anti-anti-anti-donor antibodies. The monoclonal anti-anti-anti-donor antibodies are used to make an

immunosorbant column for the purification of anti-anti-donor antibodies from the serum of the immunized prospective organ donor. The said serum is passed over the immunosorbant column, and purified anti-anti-donor antibodies are eluted from the column. The catalyst animal C in this embodiment is of a species that is suitable for making hybridomas, for example C may be a rodent animal.

[0065] Another embodiment of the present method involves immunizing a prospective organ donor A with tissue of a prospective transplant recipient B, preferably comprising

lymphocytes. For safety, the tissue of the recipient used for immunization can be gamma irradiated, for example with 3000 rads of gamma irradiation. Serum or IgG obtained from the immunized donor can be absorbed using B tissue, for example B lymphocytes, removing the anti-B and anti-anti-anti-B antibodies, and leaving serum or IgG enriched in anti-anti-A antibodies.

[0066] The anti-anti-donor antibodies can be given to the potential organ recipient in non- immunogenic form preferably starting at the time point of a skin graft from the potential organ donor. Administration of the anti-anti-donor antibodies may also be given prior to the time of skin tissue transplantation. The number of administrations that are needed may vary depending on circumstances but, for example, there may be two or more, three or more, four or more, ten or more, or twenty or more administrations of anti-anti-donor antibodies. The administrations may be at any suitable time interval. For example, the time between administrations may initially be relatively short, e.g. one or two days, then after a week or so the time intervals can be extended, e.g. doubled, and then systematically increased as needed. The dose in each given case can be varied depending on the response of the recipient. For example any inflammation at the site of the skin graft is indicative of the need for more doses of anti-anti-A antibodies or of larger doses of the anti-anti-donor antibodies. Following stable acceptance of the skin graft, the prospective organ recipient is able to accept an organ transplant from the ogan donor at any time that this is needed. These methods allow for the induction of only one way transplantation tolerance, since the donor becomes immune to the tissue of the recipient and cannot also be made transplantation tolerant with respect to tissue of the recipient.

[0067] An embodiment of the present method involves the induction of reciprocal transplantation tolerance between two vertebrates, for example between two members of a couple A and B. This embodiment allows for both A and B becoming potential organ donors for each other if and when the need should arise. This embodiment involves a third party catalyst vertebrate C as shown in Figure 5. Both A and B are immunized with tissue of C, preferably comprising lymphocytes. A makes anti-C, anti-anti-A and anti-anti-anti-C antibodies, while B makes anti-C, anti-anti-B and anti-anti-anti-C antibodies. The A and B immune sera can be absorbed using C tissue to remove anti-C and anti-anti-anti-C antobodies, leaving sera enriched in anti-anti-A and anti-anti-B antibodies respectively. The anti-anti-A antibodies can be administered in non-immunogenic form to B at the time of the application of a B skin graft and at intervals following the application of the skin graft. Similarly, the anti- anti-B antibodies can be administered in non-immunogenic form to A at the time of the application of a B skin graft and at intervals following the application of the skin graft.

Following stable acceptance of the skin grafts, A and B are mutually more transplantation tolerant with respect to the other, and each can receive an organ transplant from the other if and when needed. In this embodiment the immune systems of A and B are made optimally similar to each other, since the method is designed to make them not only tolerant to each other, but also immune to the same vertebrate C. This is therefore a preferred method, even if only one-way transplantation is intended. C may be chosen to be something very different from both A and B, for example C may be of a different species. [0068] The present disclosure provides the use of anti-anti-donor antibodies antibodies to reduce the risk of transplant rejection in a recipient by administering to the recipient animal an effective amount of anti-anti-donor antibodies in a non-immunogenic form.

[0069] If desired, and not counter-productive, administration of the compound according to the invention may be combined with more traditional and existing therapies for preventing transplant rejection.

[0070] An "effective amount" of a compound according to the invention refers to a non- immunogenic amount, for the number and periods of time necessary, to achieve the desired result; that is, selective suppression of the recipient's immune response to the donor graft. An effective amount of the compound may vary according to factors such as the health, age, sex and weight of the individual, and the species of the donor and recipient animals. The effective amount may be adjusted to provide the optimum result. It is preferred that the amount be between about 1 ng and about 10 μg of the anti-anti-donor antibodies per kilogram per administration to the recipient, or alloimmune, immunogen absorbed serum containing approximately the same total amount of IgG containing anti-anti-donor antibodies. For example an effective amount may be about 1 μg of purified anti-anti-donor antibodies, or of IgG containing anti-anti-donor antibody per kilogram per administration to the recipient, or alloimmune, immunogen absorbed serum containing approximately the same total amount of IgG.

[0071] The present disclosure provides a composition comprising the anti-anti-donor antibody in combination with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier will depend on the mode of administration of the compound but will preferably be non- immunogenic. Suitable carriers are those known in the art for use in such modes of administration.

[0072] The pharmaceutical compositions may be formulated by means known in the art and their mode of administration.

[0073] The pharmaceutical composition may comprise anti-anti-donor antibodies or fragments of antibodies in combination with a pharmaceutically acceptable carrier.

[0074] The dose of the pharmaceutical composition will be determined by the skilled practitioner. It is preferred that each dose contain between about 10 ng and about 10 μg of the anti-anti -donor antibody per kilogram weight of the recipient, or alloimmune, immunogen absorbed serum containing approximately the same total amount of IgG. For example, the dose may contain about 1 μg of the anti-anti-donor antibody per kilogram weight of the recipient per dose, or alloimmune immunogen absorbed serum containing the same total amount of IgG.

[0075] The present invention further discloses a kit comprising a pharmaceutical composition of the anti-anti-donor antibody with a pharmaceutically acceptable carrier together with instructions for administration to recipients of donor tissue.

[0076] The present disclosure further provides a method of supplying anti-anti-donor antibodies, the method comprising: a. receiving input parameters, said parameters comprising a sample of lymphocytes from a tissue donor, a sample of lymphocytes from a tissue recipient and a delivery location; b. obtaining, based on the input parameters, an appropriate anti-anti-donor antibodies for facilitating the transplantation of tissue from said donor to a recipient; and c. distributing said anti-anti-donor antibodies to the delivery location.

[0077] The present method can be used also for non-human vertebrates. For example, the method may include the production of anti-anti-donor antibodies suitable for using pigs as organ donors for humans. The method may furthermore include the production of anti-anti- donor antibodies for dogs as donors for dogs that are in need of an organ transplant.

[0078] The present method comprises distributing the antibodies to a delivery location. The distribution may be done by any suitable means. Given the time sensitivity of organ donation it is preferred that the distribution is performed in an expeditious manner.

[0079] The present disclosure provides a method, use, pharmaceutical composition and kit for preventing rejection of a transplanted tissue from a donor. The present disclosure provides a highly efficacious way of attaining selective suppression of the recipient's immune system. In certain embodiments administration of anti-anti-graft antibodies obtained from an immunized donor can specifically and robustly suppress the immune response of the recipient against the foreign antigens of the transplanted graft, without compromising the immune response of the recipient against other antigens. Further, the risk of adverse effects associated with immunosuppressant drugs currently used in preventing graft rejection is reduced.

Transplantation of organs, tissues or cells from donors of a species different from that of the recipient may also be used as a long-term, sustainable therapy for organ or tissue failure.

[0080] In part, the present disclosure provides monoclonal anti-anti-MHC antibodies. That is, an antibody that specifically binds to the variable region of an antibody that specifically binds to a MHC protein. The monoclonal antibody and the MHC-specific antibody may be derived from conversely alloimmune animals. The monoclonal antibody may specifically bind to the variable region of an antibody that specifically binds to one or glycoprotein and/or protein of the HIV virus such as, for example, gpl20, gp41 and/or p24. The antibodies herein may be used in a method for reducing the risk of HIV or SIV infection in a subject in need thereof, said method comprising administering the antibody in an immunogenic form. The antibodies herein may be utilized in a vaccine for reducing the risk of HIV infection, said vaccine comprising monoclonal anti-anti-MHC antibodies in immunogenic form. The antibodies herein may be delievered in a non-immunogenic form for the treatment or prevention of a degenerative disorder such as an autoimmune disorder, cancer, or the like. In part, the present disclosure provides the use of monoclonal anti-anti-MHC antibodies for reducing the risk of HIV or SIV infection in a subject in need thereof, the use comprising the step of administering to the subject an effective amount of the antibody and an adjuvant. The the adjuvant may be selected from aluminium hydroxide, aluminium phosphate, virosomes, squalene, QS21, MF59, and combinations thereof. The use may comprise administering monoclonal anti-anti- MHC antibodies to an organism prior to exposure of that organism to HIV. The use may comprise administering between about 10 μg and 100 μg of the antibody per dose

administered to the organism. In part, the present disclosure provides a pharmaceutical composition comprising monoclonal anti-anti-MHC antibodies and a pharmaceutically acceptable carrier. The composition may be in the form of a kit comprising a composition comprising monoclonal anti-anti-MHC antibodies and a pharmaceutically acceptable carrier; and instructions for use in an organism. The composition may be in an immunogenic or non- immunogenic form. In part, the present disclosure provides a method of supplying

monoclonal anti-anti-MHC antibodies as a vaccine for the prevention of infection with HIV, the method comprising receiving input parameters, said parameters comprising the HIV and/or SIV status of a subject and a delivery location; if the HIV and/or SIV status is negative, selecting appropriate monoclonal anti-anti-MHC antibodies for reducing the risk of the subject being infected with HIV; and distributing said monoclonal anti-anti-MHC antibodies to the delivery location. In part, the present disclosure provides a method of producing a hybridoma capable of producing a monoclonal anti-anti-MHC antibody, said method comprising selecting vertebrate organisms (P) and (Q); immunizing P with lymphocytes from Q; obtaining serum or IgG from the immunized animal P; treating said serum or IgG using Q lymphocytes to produce serum or IgG enriched in anti-anti-(MHC P)IgG; immunizing Q with lymphocytes from P; obtaining serum or IgG from said immunized animal Q; purifying anti- (MHC P)IgG and/or anti-anti-anti-(MHC P)IgG from the serum or IgG obtained in step f. using anti-anti-(MHC P)IgG; treating said anti-(MHC P) and anti-anti-anti-(MHC P) using suitable cells of P to reduce the amount of anti-(MHC P) antibodies leaving IgG enriched in anti-anti-anti-(MHC P) antibodies; making hybridomas using B cells from P that has been immunized with lymphocytes from Q; selecting anti-anti-MHC hybridomas using IgG enriched in anti-anti-anti-(MHC P) antibodies; and optionally, purifying monoclonal anti-anti- MHC antibodies from the anti-anti-MHC hybridomas. The method may comprise selecting vertebrate organisms (P) and (Q); immunizing P with lymphocytes of Q; immunizing Q with lymphocytes of P; making hybridomas using the immunized vertebrate P of step a. and selecting clones based on their anti-HIV specificity; optionally producing monoclonal antibodies from the selected hybridomas; making hybridomas using the immunized vertebrate Q of step b. and selecting clones on the basis of their V regions specifically binding to the V regions of the monoclonal antibodies produced in step d.; and optionally making monoclonal antibodies by the hybridomas selected in step e. The present disclosure provides a method of producing a monoclonal antibody, said method comprising selecting vertebrate organisms (P) and (Q); immunizing P with lymphocytes from Q; using lymphocytes from P to make hybridomas; producing and purifying monoclonal antibodies using said hybridomas;

immunizing a vertebrate animal X with the monoclonal antibodies given in immunogenic form; obtaining serum from X; testing the serum for the presence of antibodies that bind to HIV; and selecting the monoclonal antibodies that induce the production of antibodies that bind to HIV.

[0081] In part, the present disclosure provides monoclonal anti-anti-anti- antibodies. That is monoclonal antibodies that specifically binds to the variable region of an anti-anti-MHC antibody. The present monoclonal antibody and the anti-anti-MHC antibody may be derived from conversely alloimmune animals. The monoclonal antibody may bind to the HIV antigens gpl20, gp41 , p24, or a combination thereof. The present disclosure in part provides a method for producing a hydridoma capable of producing monoclonal anti-anti-anti-MHC antibodies, said method comprising immunizing an animal P with lymphocytes of an animal Q;

immunizing animal Q with lymphocytes of animal P; obtaining IgG from the immunized animal P; treating said IgG with Q lymphocytes to absorb out anti-(MHC Q) and anti-anti- anti-(MHC Q) antibodies and thus to produce IgG enriched with anti-anti-(MHC P) IgG; producing hybridomas using B lymphocytes of the immunized animal Q; selecting hybridomas that make monoclonal anti-anti-anti-(P MHC) antibodies i.e. have V regions that bind to the V regions of the anti-anti-(MHC P)IgG antibodies of step d. and do not substantially bind to P MHC antigens; optionally producing monoclonal anti-anti-anti-(MHC P) antibodies from said hydridomas. The present disclosure in part provides a method for producing hydridomas capable of producing monoclonal anti-anti-anti-MHC antibodies comprising the steps of immunizing an animal Q with lymphocytes of an animal P; making hydridomas from lymphocytes of the immunized animal Q; producing antibodies from said hybridomas; assaying said antibodies for their binding to the HIV antigens gpl20, gp41 and/or p24; optionally, confirming the anti-anti-anti-MHC specificity by testing for binding to anti-anti-P antibodies and/or lack of binding to P MHC antigens. The present disclosure in part provides the use of monoclonal anti-anti-anti-MHC antibodies in the treatment or prevention of a degenerative disease in a vertebrate animal (X) the use comprising the administration to said animal one more effective, non-immunogenic, doses of monoclonal anti-anti-anti-(X MHC) antibodies. For instance, the disease may be an autoimmune disease, cancer, or the like. The present administration may comprise about 10 ng to about 10 μg of the anti-anti-anti-donor antibodies per kilogram of the vertebrate is administered per dose. The present disclosure provides in part the use of monoclonal anti-anti-anti-MHC antibodies in the treatment of the recipient of a tissue transplant, said use comprising the administration to the recipient an effective amount of monoclonal anti-anti-anti-(donor MHC) antibodies in non- immunogenic form, where the donor is the prospective tissue donor. The recipient animal and said donor animal may be of the same or different species. The monoclonal anti-anti-anti- (donor MHC) antibodies may be administered to the recipient animal at the time of, and/or following transplantation of tissue from the donor animal to the recipient animal. The monoclonal anti-anti-anti-(donor MHC) antibodies may be administered to the recipient prior to and/or at the time of and/or following transplantation of tissue from the donor animal to the recipient animal. From about 10 ng to about 10 μg of the anti-anti-anti-donor antibodies per kilogram of the recipient may be administered per dose. The present disclosure provides in part a kit comprising a composition comprising monoclonal anti-anti-anti-MHC antibodies and a pharmaceutically acceptable carrier; and instructions for use in an animal. The present disclosure provides in part use of monoclonal anti-anti-anti-MHC antibodies in inducing mutual transplantation tolerance between two vertebrates "A" and "B" comprising

administering anti-anti-anti-(B MHC) antibodies to A and applying a B skin graft to A;

administering anti-anti-anti-(A MHC) antibodies to B and applying an A skin graft to B; and assessing when the skin grafts are stably accepted as an indication of transplantation tolerance.

[0082] It is contemplated that any embodiment discussed in this specification can be implemented or combined with respect to any other embodiment, method, composition or aspect of the invention, and vice versa.

[0083] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, all patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein

incorporated by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference. Citation of references herein is not to be construed nor considered as an admission that such references are prior art to the present invention.

[0084] Use of examples in the specification, including examples of terms, is for illustrative purposes only and is not intended to limit the scope and meaning of the embodiments of the invention herein. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to," and the word "comprises" has a corresponding meaning.

[0085] The invention includes all embodiments, modifications and variations substantially as hereinbefore described and with reference to the examples and figures. It will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. Examples of such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. [0086] The present invention will be further illustrated in the following examples. However it is to be understood that these examples are for illustrative purposes only, and should not be used to limit the scope of the present invention in any manner.

EXAMPLES

Example 1. A method for production of affinity purified anti-anti-donor antibodies wherein: a. a prospective organ donor is immunized with lymphocytes of a catalyst vertebrate C, and makes anti-C, anti-anti-donor and anti-anti-anti-C antibodies; b. vertebrate C is immunized with donor lymphocytes and makes anti-donor, anti- anti-C and anti-anti-anti-donor antibodies; c. B lymphocytes from the vertebrate C are used to make hybridomas; d. hybridomas from step c. are selected that have V regions that bind to HIV antigens. These hybridomas have V regions that are anti-HIV and are believed to be anti-anti-anti-donor; e. the hybridoma of step d. are used to make monoclonal antibodies that are believed to be anti-anti-anti-donor antibodies; f. the monoclonal anti-anti-anti-donor antibodies of step e. are used to make an immunosorbant column for the purification of anti-anti-donor antibodies from the serum of the immunized organ donor of step a.; g. serum is obtained from the immunized prospective donor donor of step a. and passed over the immunosorbant column of step f; and h. purified anti-anti-donor antibodies are eluted from the immunosorbant column.

Example 2. A method for the production of serum or IgG enriched in anti-anti-donor IgG comprising:

a. immunizing a prospective donor with allogeneic tissue, said tissue preferably comprising lymphocytes;

b. absorption of donor serum to remove antibodies specific for the allogeneic tissue, leaving serum enriched in anti-anti-donor antibodies; and c. optionally purifying the IgG that is enriched in anti-anti-donor antibodies. In this Example the organ donor and the organ recipient may be both human, the organ donor may be non-human and the organ recipient may be human, or the organ donor and the organ recipient may be both non-human animals, for example dogs.

Example 3. A method for the facilitation of an organ transplant from a donor to a recipient vertebrate, in which an effective amount of anti-anti-donor antibodies is given at the time of an organ transplant and at intervals following the transplant, specifically decreasing the immune response of the organ recipient to the transplanted organ.

Example 4. A method for the facilitation of an organ transplant wherein: a. An effective amount of anti-anti-donor antibodies is given at the time of a donor skin graft being applied to a prospective organ recipient and at intervals following the application of the skin graft. The donor and recipient may be allogenic (e.g. both human) or xenogenic (e.g. a non-human donor and a human transplant recipient). b. When the skin graft is stably accepted, the prospective recipient is transplantation tolerant to tissue of the donor, and can receive an organ transplant from the prospective donor at any time that is needed.

Example 5. A method for the facilitation of organ transplantation that involves the induction of reciprocal transplantation tolerance between two vertebrates "A" and "B" wherein: a. anti-anti-A antibodies are produced using immunization of A with lymphocytes of a catalyst vertebrate C; b. anti-anti-B antibodies are produced using immunization of B with lymphocytes of a catalyst vertebrate C; c. the vertebrate B receives an A skin graft and an effective amount of the anti-anti-A antibodies at the time of the skin graft and at intervals thereafter. d. the vertebrate A receives a B skin graft and an effective amount of the anti-anti-B antibodies beginning at the time of the skin graft and at intervals thereafter; and e. the combination of the skin graft and the anti-anti-graft antibodies takes A and B to a state in which they are each immune to C and are each tolerant to the histocompatibility antigens of the other, and are both available as organ donors for the other at any time, should this be needed.

Claims

1. A method of facilitating acceptance of a tissue transplant from a donor to a recipient, said method comprising administering to the recipient an effective amount of anti-anti- donor antibodies wherein the administration of said antibodies is non-immunogenic.

2. The method of claim 1 wherein the anti-anti-donor antibodies bind specifically to the variable region of an antibody that specifically binds to a donor MHC protein.

3. The method of claim 1 wherein the anti-anti-donor antibodies bind to anti-donor

antibodies and/or anti-anti-anti-donor antibodies present in an anti-donor serum.

4. The method of claim 1 wherein the antibodies are administered to the recipient

multiple times.

5. The method of claim 1 wherein the dose of the antibodies is from about 10 ng to about 10 μg per kilogram body mass of the recipient.

6. The method of claim 1 wherein the donor and recipient are of the same species.

7. The method of claim 1 wherein the donor and recipient are of different species.

8. The method of claim 1 wherein at least one dose of antibodies is administered to the recipient before the transplantation of the tissue.

9. The method of claim 1 wherein at least one dose of antibodies is administered to the recipient substantially simultaneously with the transplantation of the tissue.

10. The method of claim 1 wherein the tissue is an organ.

11. The method of claim 1 wherein the donor and the recipient are both humans.

12. The method of claim 1 wherein the donor is a non-human animal and the recipient is a human.

13. A method of producing anti-anti-donor antibodies, said method comprising: a. Immunizing a prospective tissue donor with lymphocytes from a vertebrate

C; b. Immunizing a vertebrate C with lymphocytes from the prospective donor; c. Making hydridomas from B lymphocytes from the vertebrate C; d. Selectng hybridomas from step c. that have V regions that bind to HIV antigens; e. Producing antibodies from the hybridomas of step d.; f. Using the monoclonal anti-anti-anti-donor antibodies of step e. to make an immunosorbant column for the purification of anti-anti-donor antibodies from the serum of the immunized organ donor of step a.; g. Obtaining serum from the immunized prospective donor of step 1 and

passing said serum over the immunosorbant anti-anti-anti-donor column of step f; and h. Eluting purified anti-anti-donor antibodies from the immunosorbant

column.

14. A method of facilitating a tissue transplant from a donor to a recipient, said method comprising: a. applying to the recipient donor tissue to serve as an indicator of tolerance; and b. administering to the recipient such a dose or doses of anti-anti-donor antibodies so as to ensure stable acceptance of the indicator tissue;

15. The method of claim 14 wherein the indicator tissue comprises donor skin cells.

16. A method for the facilitation of tissue transplantation between two vertebrates 'A' and 'B', said method comprising: a. Producing anti-anti-'A' antibodies by immunizing a catalyst vertebrate 'C with tissue from Ά'; b. Producing anti-anti-'B' antibodies by immunizing 'B' with tissue from 'C; c. Administering anti-anti-'A' antibodies to B; d. Grafting skin from 'A' onto 'B'; e. Administering anti-anti-'B' antibodies to A; f. Grafting skin from 'B' onto Ά'; wherein such a dose or doses of anti-anti- antibodies are administered so as to ensure stable acceptance of the skin grafts.

A method of producing serum enriched with anti-anti-donor antibodies, said method comprising: a. immunizing a donor organism with allogeneic tissue, said tissue preferably comprising lymphocytes; and b. absorbing donor serum to remove antibodies specific for the allogeneic tissue, leaving serum enriched in anti-anti-donor antibodies.

A method for transplanting tissue from a donor to a recipient, said method comprising the administration of an effective, non-immunogenic, amount of anti-anti-donor antibodies or IgG or serum enriched in anti-anti-donor antibodies in a non- immunogenic form.

Use of anti-anti-donor antibodies for the facilitation of tissue transplantation.

The use of claim 19 wherein the antibodies are delivered in a non-immunogenic form.