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 severity of GVHD in old APC chimeric mice. Young B6D2F1 mice r...
Increased severity of GVHD in old APC chimeric mice. Young B6D2F1 mice received 11 Gy TBI and were injected with 5 × 106 BM cells from young (2 months old) or old (18 months) B6D2F1 mice. After 3 months for hematopoietic engraftment and APC repopulation, chimeric mice were irradiated again with 7.5 Gy and injected with 5 × 106 B6 BM cells and 2 × 106 splenic T cells from B6 mice. (a) Old → young chimeric mice (triangles, n = 16) had significantly more rapid mortality than did young → young chimeras (squares, n = 16). **P < 0.003 by log rank test. (b) Clinical GVHD score was measured as described in Methods. *P < 0.05, old donors versus young donors. GVHD scores are shown as mean ± SE. (c) B6 donor T cells were labeled with CFSE as described in Methods and injected into chimeric recipients after 7.5 Gy TBI. Splenocytes were harvested and pooled (n = 3/group) on day 3 after BMT and labeled with anti-CD4 as described in Methods. ***P < 0.02. One experiment representative of two similar experiments is shown.