Transplant tolerance, similar to transplant rejection, is mediated by T cells, and activation of T cells is a prerequisite for both rejection and induction of donor-specific tolerance. Thus, costimulatory molecules play an important role in regulating rejection or acceptance of the allograft. Because of this, T-cell costimulatory molecules have been atw the forefront of transplantation research for decades. The initial paradigm was that engagement of costimulatory molecules, in the context of TCR stimulation, promotes activation, clonal expansion, survival, and effector differentiation of T cells and, therefore, their absence would have resulted in anergy and/or apoptotic cell death of activated T cells, a situation that favors transplant survival. Earlier studies, mostly using in vitro models, supported this paradigm. In fact, activation of T cells by TCR stimulation in the presence of CD28 costimulatory blockade often resulted in anergy and apoptosis of responding T cells. An implication of this finding is that by blocking costimulatory signals at a critical time of TCR stimulation, the T-cell response might be aborted, and in the setting of transplantation, rejection might be prevented, which may result in long-term allograft survival and possibly tolerance. Indeed, in selected rodent models, blocking CD28 and/or CD154 costimulation can induce prolonged allograft survival and, in some cases, donor-specific tolerance (Sayegh and Turka, N Engl J Med. 338:1813-21, 1998). These initial findings generated tremendous enthusiasm toward clinical translation in that therapeutic blockade of key costimulatory pathways may be a promising way to the induction of transplant tolerance.

Original languageEnglish (US)
Title of host publicationRodent Transplant Medicine
Subtitle of host publicationSecond Edition
PublisherSpringer Singapore
Number of pages26
ISBN (Electronic)9789811961113
ISBN (Print)9789811961106
StatePublished - Jan 1 2023


  • Costimulatory molecule
  • Tolerance induction
  • Transplant model Costimulatory signal
  • Transplant tolerance

ASJC Scopus subject areas

  • Medicine(all)
  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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