The Yin and Yang of adaptive immunity in allogeneic hematopoietic cell transplantation: Donor antigen-presenting cells can either augment or inhibit donor T cell alloreactivity

Abstract

The immunoregulatory activity of different donor bone marrow (BM) cell subsets has not yet been fully addressed in allogeneic transplantation. We studied whether manipulation of donor antigen-presenting cells (APC) can affect posttransplant immunity using a mouse model of allogeneic bone marrow transplantation (BMT). CD11b is a marker present on mature monocytes, granulocytes, and a subset of dendritic cells (DC). In order to manipulate the content of APC, we enriched or depleted CD11b+ cells from BM grafts using immuno-magnetic cell sorting. The effect of CD11b depletion on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) was studied in a MHC fully mismatched model of allogeneic BMT using C57BL/6 → B10.BR transplants and LBRM cells, a B10.BR T cell leukemia cell line. Transplantation with CD11b partially or fully depleted BM and low-dose donor splenocytes conferred 40% long-term leukemia- free survival with minimal GvHD when supralethal doses of LBRM were administered before transplant, or 75 days after BMT. Higher levels of serum gamma interferon and expansion of spleen-derived CD4+ memory T cells were seen among recipients of CD11b-depleted BM compared to recipients of unmanipulated BM. Expansion of donor-spleen-derived T cells was inversely proportional to the content of CD11b+ cells in the BM graft. Thus, manipulating the content of APC subsets in donor BM by enriching or removing CD11b+ cells had a direct effect on post-transplant immunity and the balance between donor T cell activation (Yang) and donor T cell tolerance/anergy (Yin). © 2007 Springer Science+Business Media, LLC.