CTLA4-Ig: Progress with a Novel Immunosuppressive Agent in Experimental Solid Organ Transplantation.
The process of allograft rejection is a T cell-dependent phenomenon that occurs as a result of binding of foreign antigen and major histocompatibility complex (MHC) expressed on antigen-presenting cells to the T cell receptor/CD3 complex. Evidence suggests that binding of the alloantigen-MHC complex to the T cell receptor is insufficient by itself to initiate allograft rejection and induction of T cell responses, and a second or ;costimulatory' signal is required. This costimulatory response occurs as a result of activation of a distinct T cell surface molecule, CD28, by antigen-presenting cells that express a specific surface antigen, B7, that functions as a natural ligand to CD28. A similar T cell surface molecule, encoded on human chromosome 2 adjacent to CD28 and sharing 32% homology with CD28, has been cloned and termed CTLA4. CTLA4 is a member of the immunoglobulin gene superfamily, and exists as a complex on the surface of activated T cells. A fusion protein, CTLA4-Ig, consisting of the extracellular domain of CTLA4 in combination with the constant region of the human immunoglobulin Cgamma chain, has been developed to investigate the effects of inhibition of the B7/CD28 costimulatory pathway on transplant rejection. CTLA4-Ig acts as a competitive inhibitor of CD28 by specifically binding B7 and preventing the binding of CD28 to B7. CTLA4-Ig, administered alone, has been shown to prolong graft survival in in vivo models of allo- and xeno-transplantation, as well as to potentiate the effects of other immunosuppressive agents.
Pagani
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Section of Thoracic Surgery, Department of Surgery, University of Michigan Hospitals, Ann Arbor, Michigan, USA.
Bolling
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SF