Transplant tolerance associated with a Th1 response and not broken by IL-4, IL-5, and TGF-beta blockade or Th1 cytokine administration

Karren Michelle Plain, Rochelle Boyd, Nirupama Darshan Verma, Catherine M Robinson, Giang T Tran, Suzanne J Hodgkinson, Bruce M Hall

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

BACKGROUND: Specific transplant tolerance is mediated by CD4 T cells that die unless supported by T-cell derived cytokines and donor antigen. This study examined the role of Th1 and Th2 cytokines in the maintenance of tolerance.

METHODS: Tolerance to fully allogeneic PVG cardiac allografts in DA rats was induced by short-term anti-CD3 monoclonal antibody therapy. Responses of tolerant cells to donor and third party antigen were assessed in vivo by examination of the infiltrate in the heart and application of skin grafts, and in vitro in mixed lymphocyte culture. Cell subsets were stained, induction of cytokine mRNA assayed by reverse-transcriptase polymerase chain reaction and the role of cytokines determined by treating with blocking monoclonal antibody to cytokines or cytokine administration.

RESULTS: Tolerated grafts had a T cell and macrophage infiltrate with increased mRNA for Th1 cytokines, interleukin (IL)-2, and interferon (IFN)-gamma but not Th2 cytokines. Peripheral lymphocytes proliferated in mixed lymphocyte culture and expressed Th1 cytokine mRNA. Tolerant hosts accepted PVG and rejected Lewis skin allografts and the lymph nodes draining both these grafts had similar induction of Th1 and Th2 cytokine mRNA. Treatment of tolerant rats with Th1 cytokines IL-2, IFN-gamma, and IL-12p70 or monoclonal antibody that blocked IL-4, IL-5, and transforming growth factor-beta did not prevent acceptance of PVG skin grafts.

CONCLUSIONS: These studies in a model of tolerance regulated by CD4CD25 T cells demonstrated there was no defect in Th1 responses. Tolerance was due to regulation that was not solely dependent on IL-4, IL-5, or transforming growth factor-beta and was not inactivated or overwhelmed by administration of Th1 cytokines, IL-2, IFN-gamma or IL-12p70.

Original languageEnglish
Pages (from-to)764-73
Number of pages10
JournalTransplantation
Volume83
Issue number6
DOIs
Publication statusPublished - 27 Mar 2007
Externally publishedYes

Keywords

  • Adjuvants, Immunologic
  • Animals
  • Antibodies, Monoclonal
  • Cytokines
  • Heart Transplantation
  • Interferon-gamma
  • Interleukin-12
  • Interleukin-2
  • Interleukin-4
  • Interleukin-5
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger
  • Rats
  • Rats, Inbred Lew
  • Rats, Inbred Strains
  • Skin Transplantation
  • Th1 Cells
  • Transforming Growth Factors
  • Transplantation Tolerance
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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