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Transplant Tolerance, Not Only Clonal Deletion.

Bruce M Hall1, Nirupama D Verma1, Giang T Tran1

  • 1Immune Tolerance Laboratory, School of Medicine, University of New South Wales (UNSW) Sydney, Ingham Institute, and Renal Service and Multiple Sclerosis Clinic, Liverpool Hospital, Liverpool, NSW, Australia.

Frontiers in Immunology
|May 9, 2022
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Summary
This summary is machine-generated.

Understanding transplant tolerance has evolved beyond Clonal Deletion theory. Research highlights T regulatory cells and "split tolerance" in animals, crucial for preventing immune rejection and inducing long-term acceptance of allografts.

Keywords:
chimerismclonal deletiongraft versus host diseaseregulatory T (Treg) cellstransplant tolerance

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Area of Science:

  • Immunology
  • Transplantation Biology
  • Immune Tolerance

Background:

  • The Clonal Deletion theory, dominant since the 1950s, explained immune tolerance but didn't account for all observations.
  • Early immunology lacked understanding of lymphocytes and T cell roles in graft rejection.
  • Newer research considers T regulatory cells and their role in preventing autoimmunity and transplant rejection.

Purpose of the Study:

  • To reassess Clonal Deletion theory in light of T regulatory cells.
  • To review the induction and characteristics of "operational tolerance" in animal models.
  • To explore the mechanisms underlying alloantigen-specific tolerance and "split tolerance".

Main Methods:

  • Review of historical research on Clonal Deletion theory.
  • Analysis of studies on operational tolerance in rodents and pigs, including spontaneous and therapy-induced cases.
  • Investigation of "split tolerance" phenomena, excluding antibody-mediated and anti-idiotypic mechanisms.
  • Examination of T cell transfer experiments demonstrating split tolerance.
  • Review of research identifying CD4+CD25+ T regulatory cells and their role.

Main Results:

  • Operational tolerance exhibits alloantigen-specific acceptance of grafts while retaining third-party graft rejection capacity.
  • Split tolerance indicates no clonal deletion, as peripheral lymphocytes remain reactive.
  • T cells mediate split tolerance and can transfer this capacity to naive hosts.
  • CD4+CD25+ T regulatory cells are identified as key mediators of transplant tolerance.
  • Specific T cell cytokines, beyond IL-2, are crucial for T regulatory cell survival and expansion.

Conclusions:

  • Clonal Deletion theory is insufficient to explain all aspects of transplant tolerance.
  • Operational tolerance and split tolerance are mediated by antigen-specific T regulatory cells.
  • T regulatory cells, supported by specific cytokines, are central to achieving and maintaining transplant tolerance.
  • Further research is needed to define methods for inducing and diagnosing operational tolerance.