The use of monoclonal antibodies for immunomodulation in transplantation

The genes responsible for acceptance or rejection of an allograft were called histocompatibility genes, the mist important being the Major Histocompatibility Complex, called H-2 in mice and HLA in humans. The high polymorphism of the HLA system leads to great difficulties to find unrelated fully compatible individuals so that organ allografts are mainly performed between partially histocompatible donor and recipient pairs. The recognition of foreign tissue is first mediated by the recipient T helper CD4+ lymphocytes which bind the (allo-MCH class II + peptide) complex on the surface of the donor dendritic cells. The antigenic signal for T cell activation requires the interaction between the T cell receptor complex (TCR/CD3) and the antigenic peptide presented in the context of major histocompatibility complex (MHC) proteins. To fully activate quiescent T cells, TCR/CD3-MHC interaction is necessary but insufficient and costimulatory signals are required. Proteins expressed on the T cell surface and their ligands on the surface of APC, as the CD2 and CD28 molecules on the T cells and the LFA-3 and B7 respectively on the APC, represent costimulatory signals necessary for T cell activation. That T cell surface molecules in addition to the TCR/CD3 complex must be engaged for full T cell activation offers new opportunities for the regulation of the antiallograft response. After antigenic recognition, activated CD4 cells express IL2 receptors (IL2R) and produce IL2 inducing activation and proliferation of presensitized CD8+ cytotoxic T cells recognize MHC class I antigens on the graft target cells and destroy them. The therapeutic protocols available to control transplant rejection result in a high incidence of undesirable side effects due to non specific depression of immune responses but also of cells not directly involved with immunity or immune responses but also of cells not directly involved with immunity or releasing unwanted factors after activation. Transplantation research has been directed to identification of agents with a more predictable impact upon the immune system. One significant advance occurred with the introduction of polyclonal antilymphocyte preparations (ALG, ATG, …) produced by immunizing rabbits or horses with human thymocytes or lymphocytes. Following the discovery of the hybridoma technology b y Köhler and Milstein in 1975, Kung et al at Ortho Pharmaceutical Corporation (Raritan, USA) developed a panel of monoclonal antibodies (MoAb) to human T cell surface antigens, the OKT series. Among them, OKT3, a murine MoAb of the IgG2a isotype was directed against a glycoprotein (20 Kd invariant epsilon portion) of the CD3 complex expressed on human T mature lymphocytes and involved in signal transduction. Very rapidly, OKT3 MoAb was shown to be a powerful immunosuppressive agent in all types of allografts and is still the only MoAb commercially available for administration in transplant patients. The use of either polyclonal or MoAb against pan-T cell markers becomes a standard practice for promoting graft stability and rejection treatment. The advent of MoAb should solve the problems encountered with the polyclonal reagents i.e. the broad reactivity to both T and non T cells, the variations from batch to batch and the substantial amount of irrelevant antibodies. A number of MoAb recognizing accessory or activation molecules have been tested as immunotherapeutic agents for transplant rejection. The specificities against which these MoAbs are directed include CD2, CD4, CD11&, CD25, CD54, CD53, CD80. clinical trials were disappointing for some of them and are still ongoing for others such as CD2, CD4, CD11 and CD54. Among the rat anti human MoAbs which have been produced in the Experimental Immunology Unit, two of them showed interesting immunosuppressive proteins in vitro and were developed for clinical use. LO-Tact-1 is a MoAb (rat IgG2b) directed against the p55 chain of the human IL2 receptor (IL2R). This MoAb was obtained byt the somatic fusion of LOU/C rats splenic cells immunized with PHA stimulated human peripheral blood lymphocytes (PBL-PHA) and the non secreting rat fusion line IR983F. It precipitates a 63kDa antigen expressed on activated lymphocytes and inhibits IL2 binding on activated T lymphocyte cultures (MLC) and no activation of resting cells. LO-Tract-1 MoAb, as many rat IgG2b antibodies, was able to mediate an antibody dependent cell mediated cytotoxicity (ADCC) inducing lysis of activated human lymphocytes by killer cells. In kidney transplantation, LO-Tract-1 MoAb, at a dose of 10 mg/day, was very well tolerated but did not show any efficacy in rescue rejection treatment. It was used, at the same dose, in prophylactic treatment of kidney transplanted patients in association with Cyclosporine A (CsA), steroids and Azathioprine and was shown to have a similar effect as ALG. […]Thèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 199