Abstract:

Since active clinical transplantation became a reality, physicians have been in constant conflict with the body's immunologic defenses. Steroids and azathioprine were the mainstay of immunosuppressive therapy for many years. During these years, graft survival was modest, with survival rates of 50% or less at one year for cadaver transplants. After the introduction of cyclospor ine A in 1983, renal cadaver graft survival rates increased to 60-75%. Since that time, other immunosuppressive agents such as OKT3 and better patient management have increased 1-year graft survival rates well above 80%. Nevertheless, present immunosuppressive regimens remain toxic, nonspecific, and render the patient at increased risk of infection and lymphoproliferative disorders. Presently there exists no "magic bullet" that can render the immune system incapable of rejecting a graft while allowing the patient continued defense against infection. However, a new drug, mycophenolate mofetil (MMF; CellCept®;RS-61443)comes surprisingly close to this concept by emphasizing a unique mechanism of action.

Authors:

Carlton J. Young, M.D., University of Arizona School of Medicine, Tucson, AZ; Hans W. Sollinger, M.D., Ph.D., University of Wisconsin School of Medicine, Madison, WI

For Direct IP Access please click this link

Abstract:

Activated T cells playa central role in the rejection of histo incompatible organ allografts. Studies of transmembrane signaling requirements ofT cells, by identifying molecular and cellular mechanisms ofT-cell activation, can lead to rational therapeutic strategies for the regulation of the anti-allograft response. A clear consensus exists that the primary signal for T-cell activation is generated as a consequence of the interactions among the T-cell receptor for antigen (TCR)I cluster designation 3 (CD3) complex and the antigenic peptide presented in the context of major histocompatibility complex (MHC) proteins expressed on the surface of the antigen-presenting cells (APCs). The TCR/CD3-dependent signaling is necessary but insufficient in itself to fully activate normal human primary (quiescent) T cells, and additional costimulatory signals are required for full activatiori.

Authors:

Timothy Gayowski, M.D., F.R.C.S.(C.), F.A.C.S; Ignazio R. Marino, M.D., F.A.C.S.; Nina Singh, M.D.,; Howard R. Doyle, M.D.; Marilyn M. Wagener, M.P.H.; Satoru Todo, M.D.; John J. Fung, M.D., Ph.D.; Thomas E. Starzl, M.D., Ph.D.; Pittsburgh Transplantation Institute and the Vetrans Administration Medical Center, Pittsburgh, Pennsylvania

For Direct IP Access please click this link