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.
View: Text | PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Age exacerbates GI tract GVHD and increases serum LPS and TNF-α. B6D2F1 ...
Age exacerbates GI tract GVHD and increases serum LPS and TNF-α. B6D2F1 mice were transplanted as described in Figure 1 legend. Small bowel histology at day 7 in BMT recipients conditioned with 11 Gy TBI. Coded slides were evaluated for villus blunting, crypt destruction, loss of enterocyte brush border, luminal sloughing of cellular debris, and lamina propria lymphocytic infiltrate. Tissue damage of old syngeneic mice was minimal (a). The small bowel of old allogeneic mice (c) exhibited more severe villus blunting, crypt destruction changes, crypt atrophy, and increased lymphocytic infiltrate than did that of young allogeneic mice (b). Original magnification: ×200. (d) Pathology index. Coded slides from each group (old syngeneic [gray bar], young allogeneic [white bar], and old allogeneic mice [black bar]) were scored for each parameter on a scale of 0–4 and summed (n = 4 in each group). *P < 0.03, young versus old allogeneic mice. (e and f) Mice were transplanted as in Figure 1 and serum was obtained by performing heart puncture on day 7 after BMT. LPS (e) and TNF-α (f) data represent the mean ± SE of 9 young (white bar) and 9 old (black bar) animals **P < 0.01, ***P = 0.03, young versus old allogeneic mice. Data were combined from animals transplanted in two separate experiments. Path index, pathology index; syn, syngeneic; allo, allogeneic. ND, not detected.