Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
Rainer Ordemann, Raymond Hutchinson, Jeffrey Friedman, Steven J. Burakoff, Pavan Reddy, Ulrich Duffner, Thomas M. Braun, Chen Liu, Takanori Teshima, James L.M. Ferrara
Rainer Ordemann, Raymond Hutchinson, Jeffrey Friedman, Steven J. Burakoff, Pavan Reddy, Ulrich Duffner, Thomas M. Braun, Chen Liu, Takanori Teshima, James L.M. Ferrara
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Article Immunology

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease

Abstract

Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-α and IL-12 after LPS stimulation. In a B6 → B6D2F1 model, CD4+ donor T cells but not CD8+ T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.

Authors

Rainer Ordemann, Raymond Hutchinson, Jeffrey Friedman, Steven J. Burakoff, Pavan Reddy, Ulrich Duffner, Thomas M. Braun, Chen Liu, Takanori Teshima, James L.M. Ferrara

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Increased T cell responses to old host APCs. (a) Nonirradiated young and...
Increased T cell responses to old host APCs. (a) Nonirradiated young and old B6D2F1 mice were injected with 5 × 107 splenic lymphocytes from B6.Ly5.2 donors for expansion studies. Spleens were harvested on day 4. Donor T cell phenotype (CD4+, CD8+, and CD45.1+) was determined by FACS analysis as described in Methods. (b–d) Young splenic T cells from B6 mice were cultured with irradiated spleen cells from either young B6D2F1 or old B6D2F1 animals. Proliferation and IL-2 and IFN-γ production were measured as described in Methods. (e) BM-derived DCs were irradiated and cultured with 1 × 105 T cells from B6 mice as described in Methods. T cell proliferation was determined by [3H]thymidine incorporation. P < 0.01, allogeneic T cell responses to old DCs (filled squares) versus young DCs (open squares). (f and g) TNF-α and IL-12 p40 secretion from DCs stimulated with 0.1 μg LPS/ml for 4 hours (TNF-α) or 24 hours (IL-12 p40). Each graph represents one of three similar experiments. *P = 0.03, **P < 0.01.