Prevention of lethal acute GVHD with an agonistic CD28 antibody and rapamycin

Blood. 2005 Feb 1;105(3):1355-61. doi: 10.1182/blood-2004-08-3305. Epub 2004 Sep 30.

Abstract

Successful hematopoietic cell transplantation (HCT) from an allogeneic donor ideally should produce tolerance to recipient alloantigens while preserving anti-infectious and antitumor immunity. Rapamycin together with costimulation blockade can induce tolerance in organ allograft models by inhibiting G(1) --> S-phase progression and promoting T-cell apoptosis. In contrast to blocking costimulation through CD28, administration of agonistic CD28-specific antibody 37.51 partially prevents lethal graft-versus-host disease (GVHD) by selective depletion of alloreactive T cells in mice. We hypothesized that combining rapamycin with agonistic CD28 treatment would improve GVHD control by tolerizing a small subset of alloreactive T cells that might escape effects of the CD28-specific antibody. A short course of rapamycin plus agonistic CD28 treatment showed synergism at suboptimal doses, was highly effective in preventing lethal GVHD, and was superior to rapamycin plus CD28 blockade in a major histocompatibility complex class I- and II-mismatched HCT model. The combination treatment reduced the number of proliferating, alloreactive cells in the recipient, promoted donor B- and T-cell reconstitution, and reduced inflammatory cytokine levels. Administration of rapamycin plus agonistic CD28 antibodies offers a promising new therapeutic approach to facilitate tolerance after HCT.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody Specificity
  • CD28 Antigens / immunology*
  • Graft vs Host Disease / prevention & control*
  • Immunosuppression Therapy / methods
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Sirolimus / therapeutic use*
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Monoclonal
  • CD28 Antigens
  • Sirolimus