Transplant rejection. Mechanisms and treatment
C. Chandler and E. Passaro Jr
Surgical Service, Veterans Affairs Medical Center, Los Angeles, CA 90073.
In this review, we summarize the cellular and molecular events in the
rejection of transplanted allografts, as well as the rationale for the
evolving techniques to suppress such rejection. Allogenic major
histocompatibility complex antigens expressed on the allograft and/or on
the "passenger leukocytes" within the graft are the major antigenic stimuli
recognized as being foreign by receptors of CD4+/T helper cells of the
host. Host macrophages provide a second signal, interleukin (IL) 1,
essential to the activation of T helper cells. Subsequent production of
IL-2 by T helper cells leads to activation and proliferation of cytotoxic T
cells and lymphokine-activated killer cells and the release of IL-4 and
IL-6. In addition, IL-2 promotes release of interferon gamma as well as
tumor necrosis factor and other proinflammatory cytokines. Therapeutic
options to "downregulate" this cascade have gradually evolved from global
nonspecific immunosuppressive techniques (total body irradiation,
antilymphocyte serum) to increasingly specific modalities currently being
studied, including monoclonal antibodies against the IL-2 receptor (thus
targeting only vigorously proliferating T cells), antibodies against
specific cytokines (interferon gamma, tumor necrosis factor), and now
"designer" antibody-toxin conjugate molecules that deliver toxins to
selected receptor targets. Finally, work continues toward inducing
preoperative antigen-specific (graft) tolerance, including utilization of
gene transfection techniques to transfect donor major histocompatibility
complex antigens to recipients before surgery, which has been shown to
prolong murine cardiac allografts, perhaps by priming specific suppressor
cells. Further understanding of the initiation of, and subsequent events
in, transplantation rejection will lead to increasingly effective
prolongation of graft survival while minimizing adverse effects on the
host.
