ABSTRACT
Rejection by the host’s immune system represents the main barrier to successful transplantation of allogeneic organs and tissues. The development of immunosuppressive drugs in the 1960s has permitted the large-scale transplantation of some organs such as kidneys and livers by preventing their early acute rejection. However,
Abstract .................................................................................................................. 167 Introduction ............................................................................................................ 168 Induction of Transplant Tolerance Using Donor MHC Proteins and Peptides ...... 170
Transplantation Tolerance Using Intact Donor MHC Proteins ......................... 170 Transplantation Tolerance with MHC Peptides ................................................ 170
Peptides Derived from Polymorphic Regions of MHC Class I Molecules ......................................................................................... 171 Peptides Derived from Polymorphic Regions of MHC Class II Molecules ........................................................................................ 171 Peptides Derived from Conserved Regions of MHC Molecules .................. 171
Modulation of Autoimmunity to Tissue-Specic Antigens ................................... 172 Prevention of Allotransplant Rejection Using Monoclonal Antibodies ................. 173
Antibodies Directed to Surface Receptors on Immune Cells ............................ 173 Costimulation Blockade Using Antibodies .................................................. 173 Antibodies Against Other Receptors on B and T Cells ................................ 176 Antibodies Directed to Cytokines ................................................................ 177
Protein-Based Therapies in Clinical Transplantation............................................. 179 Conclusions ............................................................................................................ 181 References .............................................................................................................. 182
such treatment is associated with increased risks for infection and neoplasia. In addition, it is often toxic and ineffective in achieving long-term graft survival. Chronic allograft rejection is also a critical barrier to successful long-term survival of allotransplanted tissues and organs in patients. It is a slow process involving perivascular inammation, brosis, and intimal hyperplasia leading to lumenal occlusion of graft vessels or bronchioles in the case of lung transplants. At present, there is no treatment to prevent or block the chronic rejection process. These observations underscore the need for the design of novel and more selective treatments in transplantation. During the past two decades, a number of protein-based therapies have been developed in an effort to suppress donor-specic T cells involved in acute and chronic rejection of allografts. In experimental models, successful transplant tolerance induction has been achieved using soluble major histocompatibility complex (MHC) proteins and peptides, presumably via the induction of host’s regulatory T cells capable of suppressing proinammatory antidonor immunity. Recently, some studies have shown that immune deviation of the immune response to graft tissuespecic antigens can also prolong allotransplant survival. In addition, many attempts have been made to modulate alloreactive T-cell responses using monoclonal antibodies (mAbs) directed to different receptors and cytokines involved in T-cell activation. In rodent and nonhuman primate models, some success has been achieved using antibodies blocking signals delivered via the CD28 and CD40 pathways. In clinical transplantation, non-FcR-binding humanized anti-CD3 antibodies have been shown to suppress acute rejection episodes and are still regularly used in patients. Novel antibodies directed to T and B cells such as anti-CD2, anti-CD20, anti-CD25, and anti-CD154 antibodies are currently being evaluated in clinical trials for their ability to prolong the survival of solid organ allotransplants in patients.
