Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
Rainer Ordemann, … , Takanori Teshima, James L.M. Ferrara
Rainer Ordemann, … , Takanori Teshima, James L.M. Ferrara
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1249-1256. https://doi.org/10.1172/JCI14793.
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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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Figure 1

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Reduced survival and increased severity of GVHD in older recipients afte...
Reduced survival and increased severity of GVHD in older recipients after allogeneic BMT. (a) Very old (filled circles, n = 5), old (filled triangles, n = 20), and young (filled squares, n = 16) B6D2F1 mice underwent allogeneic BMT as described in Methods. Very old B6D2F1 (open circle, n = 3) and old (open triangle, n = 7) mice that received syngeneic BMT served as negative GVHD controls. Very old B6D2F1 recipients had significantly more rapid mortality than old recipients (***P = 0.03), and old recipients died significantly faster than young recipients did (**P < 0.005). Syngeneic control mice exhibited 100% survival during the observation period (circles and triangles). (b) Very old (filled circles, n = 9), old (filled triangles, n = 17), and young (filled squares, n = 17) CBA mice were transplanted from B10.BR donors in the same fashion described above. Very old CBA mice that received syngeneic BMT served as negative GVHD controls (open circle, n = 7). Very old CBA mice had greater mortality than old mice had (P = 0.2), and old mice died more quickly than young mice (**P = 0.01). Syngeneic mice exhibited 100% survival during the observation period.