Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation.

Abstract

Delayed immunologic recovery after allogeneic bone marrow transplantation (BMT) represents a major cause of morbidity and mortality that limits the overall success of the transplantation procedure. Recent clinical data suggest that a subset of donor dendritic cells may inhibit the graft-versus-tumor activity of donor T cells. We studied the immunoregulatory activity of donor dendritic cells in allogeneic BMT between major histocompatibility complex-disparate strains of mice. Bone marrow grafts enriched or depleted of CD11b- and CD11b+ dendritic cell subsets by immunomagnetic cell sorting were combined with small numbers of congenic splenic T cells. Recipients of CD11b-depleted bone marrow had significant posttransplantation expansion of donor spleen-derived CD4+ memory T cells compared with recipients of unmanipulated bone marrow. CD11b depletion enhanced the antitumor activity of the splenic donor T cells without producing significant graft-versus-host disease and resulted in long-term survival after a supralethal dose of T-cell leukemia administered after BMT. Expansion of donor spleen-derived T cells was proportional to the number of CD11b- dendritic cells in the bone marrow graft and was associated with increased levels of serum interferon-gamma. Thus, manipulating the content of donor antigen-presenting cells in allogeneic BMT is a novel strategy to activate donor memory T cells and enhance allogeneic graft-versus-leukemia effects with minimal graft-versus-host disease.