Organ transplantation in humans achieved a considerable degree of success over the past 30 years, primarily through technical improvements and the development of better immunosuppressive drugs. Nevertheless, all organ transplants currently performed rely on chronic pharmacological immunosuppression of a nonspecific nature to prevent rejection of allografts. Because of the nonspecific nature of these drugs, and the need for ongoing therapy, patients pay a substantial price for chronic immunosuppression in the way of both toxic side effects of the individual drugs and infections and malignancy. About 4 - 6% or organ transplants are lost annually due to rejection despite these drugs. A method has been developed by the Principal Investigator to use an immunotoxin, anti-CD3-CRM9, which given in three doses prior to the transplant permits immunologic tolerance to an organ transplant without any subsequent immunosuppressive drugs. The recipients appear to be normal in every respect and able to resist environmental pathogens. The immunotoxin, developed by Dr. David Neville, a collaborator at the NIH, is a potent means of transiently killing t- lymphocytes while permitting their gradual reconstitution over a period of about 3 - 6 weeks. When allogeneic kidney transplants are performed during this window of T-cell depletion, especially in combination with thymic manipulation, long term allograft tolerance develops. The objective of this proposal is to define the mechanism of tolerance induced by this immunotoxin. Specifically, we will seek to define the degree of T-cell depletion required to produce tolerance, the role of the thymus in this phenomenon, the impact of age and thymic involution on tolerance induced with immunotoxin, and the impact of such treatment of the immune repertoire of treated recipients. Importantly, this drug developed at the NIH has the potential to replace the current strategies of immunosuppression used in organ transplantation and to render organ transplant recipients tolerant, without the need for ongoing drug therapy. The goal of this proposal would be to develop adequate preclinical data to permit phase I and II clinical trials in organ transplant recipients.
|Kwun, J; Oh, B C; Gibby, A C et al. (2012) Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment. Am J Transplant 12:2641-51|
|Torrealba, Jose R; Katayama, Masaaki; Fechner Jr, John H et al. (2004) Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1+CD4+ T regulatory cell infiltrates. J Immunol 172:5753-64|
|Torrealba, Jose R; Fernandez, Luis A; Kanmaz, Turan et al. (2003) Immunotoxin-treated rhesus monkeys: a model for renal allograft chronic rejection. Transplantation 76:524-30|
|Fechner Jr, J H; Dong, Y; Hong, X et al. (2001) Graft survival in a rhesus renal transplant model after immunotoxin-mediated T-cell depletion is enhanced by mycophenolate and steroids. Transplantation 72:581-7|
|Hamawy, M M; Tsuchida, M; Manthei, E R et al. (1999) Activation of T lymphocytes for adhesion and cytokine expression by toxin-conjugated anti-CD3 monoclonal antibodies. Transplantation 68:693-8|