Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: A method to ameliorate graft-versus-host disease and extend the donor pool

Graft-versus-host disease (GVHD) is initiated by adoptively transferred donor T cells that recognize host alloantigens. Whereas the absence of donor T-cell proliferation to host alloantigens in a mixed-leukocyte reaction does not predict freedom from GVHD, the frequency of alloreactive precursor helper T lymphocytes (pHTL) is predictive. Complete blockade of B7 family-mediated costimulation, but not of major histocompatibility complex recognition or adhesion, induces host alloantigen-specific anergy by reducing cytokine production below threshold levels necessary for common gamma-chain signaling. The associated reduction of alloreactive pHTL frequency below that predictive for GVHD, without depletion of either nonallospecific T cells or hematopoietic progenitors, has led us to embark upon human clinical trials of haplomismatched allogeneic bone marrow transplantation. (C) 1996 by The American Society of Hematology.