Blood 2002 Jun 15;99(12):4601-4609
Taylor PA, Friedman TM, Korngold R, Noelle RJ, Blazar BR.
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis; Kimmel Cancer Institute, Thomas Jefferson Medical College, Philadelphia, PA; Department of Microbiology, Dartmouth Medical College, Hanover, NH.
We previously reported that ex vivo blockade of the CD40:CD40L costimulatory pathway in primary mixed lymphocyte reaction cultures resulted in profound in vitro secondary hyporesponsiveness and 30-fold or greater protection from graft-versus-host-disease (GVHD) lethality.
Present studies demonstrate that tolerance induction via costimulatory blockade also results in the generation of a potent immunoregulatory cell that inhibits both naive and primed alloresponses.
The immunoregulatory capacity was dependent upon cell-to-cell contact that prevented the full activation of the naive or primed cells.
The inhibitory effect of tolerized cells did not preclude the response of naive T cells to nominal protein antigen if antigen was present at high concentration.
However, under suboptimal antigen concentration, nonspecific inhibition of responses occurred.
The tolerized regulatory cell population maintained a polyclonal T-cell receptor Vbeta repertoire that was broader than in control primed cultures.
These data, the first to demonstrate that tolerance induction via CD40:CD40L costimulatory blockade results in potent regulatory function, are relevant to bone-marrow and solid-organ transplantation.
The generation of potent immunoregulatory capacity during tolerization via CD40:CD40L blockade provides a fail-safe mechanism to control alloreactive T cells that may have escaped tolerization.
These potent regulatory cells may be clinically exploitable for the treatment and prevention of GVHD or autoimmunity.