Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody can prevent rat cardiac allograft rejection

J Heart Lung Transplant. 2008 Apr;27(4):362-71. doi: 10.1016/j.healun.2008.01.004.

Abstract

Background: It is well known that CD4(+)CD25(+) regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. Therefore, therapeutic agents that capable of enhancing the number and activity of this T-cell subset are highly desirable.

Methods: The present study was designed to investigate the effects of superagonistic CD28-specific monoclonal antibody (supCD28 MAb) on preferentially expanded rat naturally occurring CD4(+)CD25(+) Treg (nTreg) cells and its applicability in cardiac transplantation.

Results: A single administration of supCD28 MAb preferentially proliferated nTreg cells. The increase of Foxp3 expression and polarization toward a Th2 cytokine profile correlated with decreased production of interferon-gamma and increased production of interleukin-4 and -10 in the expanded CD4(+)CD25(+) Treg subset, which was capable of suppressing CD4(+)CD25(-) T-cell proliferation after purification. Furthermore, supCD28 MAb administration revealed that nTreg cells were preferentially proliferating in vivo and recruited into the grafts, resulting in significant prolongation of full MHC-mismatch cardiac graft survival.

Conclusions: Our data demonstrate that supCD28 MAb targets expansion of nTreg cells in vivo and maintains and enhances their regulatory functions, which represents a major advance toward the therapeutic use of polyclonally activated Treg cells as cellular therapy for treatment of allograft rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Blood Cells / metabolism
  • CD28 Antigens / immunology*
  • Cell Proliferation / drug effects
  • Concanavalin A / pharmacology
  • Forkhead Transcription Factors / metabolism*
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects
  • Heart Transplantation*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukins / metabolism
  • Isoantigens / pharmacology
  • Male
  • Myocardium / metabolism
  • Myocardium / pathology
  • Postoperative Period
  • Rats
  • Rats, Inbred Strains
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology*
  • Time Factors
  • Transplantation, Heterotopic

Substances

  • Antibodies, Monoclonal
  • CD28 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, rat
  • Interleukin-2 Receptor alpha Subunit
  • Interleukins
  • Isoantigens
  • Concanavalin A