Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA). Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver. Although nonspecific effector cells and Th1 cytokines have been shown to participate in disease induction, the role of T cells has not been fully elucidated. Initial studies demonstrated significant increases in CD4+ T cells, but not other T cell populations in the colons of diseased animals relative to transplant control animals. To demonstrate a functional linkage between increases in colonic CD4+ T cells and disease induction, in vivo T cell depletion studies were performed. Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days. Treatment with anti-CD4, but not anti-CD8, eliminated clinical symptoms and colon pathology. Interestingly, neither anti-CD4 nor anti-CD8 therapy affected the development of liver pathology associated with SGVHD. These findings demonstrated that CD4+ T cells initiate development of the intestinal inflammation associated with murine SGVHD.

Syngeneic graft-vs.-host disease (SGVHD) develops in rodents following the treatment of lethally irradiated, bone marrow (BM) reconstituted animals with a short course of the immunosuppressive agent cyclosporine A (CsA). Using an in vivo depletion approach, we recently demonstrated that CD4(+), but not CD8(+), T cells participated in inducing SGVHD. Studies were therefore undertaken to adoptively transfer SGVHD into lethally irradiated, syngeneic BM reconstituted secondary recipients. Whole T cell populations as well as purified CD4(+)T cells isolated from SGVHD, but not normal or transplant control, animals mediated the transfer of SGVHD into secondary recipients. These cells have an apparent specificity for enteric bacterial antigens. The pathologic process that developed was identical to that observed in the animals with de novo SGVHD after syngeneic BMT and CsA therapy. It was shown that a radiation-sensitive mechanism prevented the transfer of SGVHD into normal, nonirradiated secondary recipients. The ability to reproducibly transfer SGVHD into secondary recipients will enhance our ability to study regulatory mechanisms that are altered during CsA therapy and permit the development of murine CsA-induced SGVHD.

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Summary:mia responses. 1,2 Although donor T cells are clearly responsible for the initiation of GVHD, both the afferent and efferent phases of the disease appear to be dominated by The incidence and severity of GVHD following bone marrow transplantation increases with recipient age.non-specific effector cells (NK, macrophage) and proinflammatory cytokines, particularly tumor necrosis factor-␣ The role of recipient age on the development of GVHD was analyzed in a semi-allogeneic (C57BL/6 → (TNF␣) and interleukin-1 (IL-1). 2,5 Several risk factors including alloimmune female into (C57BL/6 ؋ DBA/2)F1) murine GVHD system. Young adult (2 months) and old (12-14 months) recipient mice male transplantation, degree of HLA identity, age of the recipient, GVHD prophylaxis and BM dose have been were lethally irradiated and reconstituted with young adult T cell-depleted bone marrow (ATBM) or ATBM shown to be associated with an increased risk of developing acute and chronic GVHD. 6,7 In older patients, an increased and young spleen cells. A significantly higher percentage of old vs young recipients developed lethal GVHD. Furincidence of and mortality from GVHD has been observed. [8][9][10][11] This age-related increase in GVHD has been thermore, while pre-transplant conditioning with irradiation was not required to observe increased morshown to occur as early as 20 years and is of such magnitude by 50 years of life, that few BM transplants are done tality in old recipients, irradiation predisposed the older animals for a more severe course of GVHD, suggesting despite its potential usefulness in the treatment of many neoplastic diseases. 1,8,9 With these findings in mind, it has that GVHD occurred in old compared to young animals in the absence of pre-transplant conditioning but was been proposed that the increased incidence of GVHD in old recipients may be the result of altered tolerance induction exacerbated by irradiation. Histologically, the immunological responses in the GVHD target organs were more following BMT. 12 While numerous clinical studies cite recipient age as a severe in the old GVHD animals. In support of this observation, increased spontaneous proliferation was major predisposing factor for GVHD, little to no research has been conducted in animal models to address this issue. observed using lymphoid cells isolated from old vs young GVHD mice. These findings demonstrate that old Previous studies have concentrated on donor age, where Uphoff 13 found no association between increasing donor recipients develop a more severe course of GVHD following BMT, and may present a unique opportunity to age and the risk of GVHD in mice. In this report, we describe the development of a murine GVHD model to study age-related factors in the generation of GVHD. Keywords: bone marrow transplantation; recipient age; address the role of recipient age in the GVHD process. Data will be presented demonstrating that old irradiated recipigraft-versus-host disease ents of young donor lymphoid cells have a higher incidence of acute GVHD...

These results demonstrate that after lethal irradiation and in the absence of donor T cells, T cells of recipient origin can expand and mediate the induction of CsA-induced SGVHD.

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Syngeneic graft‐vs‐host disease (SGVHD) is induced by reconstituting lethally irradiated mice with syngeneic bone marrow followed by a 21 day treatment with the immunosuppressive agent cyclosporine A (CsA). Symptoms of the disease appear 2–3 weeks following cessation of CsA therapy and disease‐associated inflammation occurs primarily in the colon and liver. Irradiation and CsA are both required for the development of SGVHD and both contribute to the production of oxidative stress. Time course studies revealed increased reactive oxygen and nitrogen species in CsA treated animals compared to BMT controls. Studies also demonstrated increased migration of CD4+T cells into the colon during CsA therapy. In addition, increased colon mRNA levels of proinflammatory cytokines (TNF‐α, IL‐12) and cell adhesion molecules (CAMs) were observed as early as day 14‐post BMT in colon of CsA treated animals. Since reactive oxygen species (ROS) are known to mediate CsA toxicity, studies were undertaken to determine the effect of CsA‐induced oxidative stress on the induction of SGVHD. Treatment with the antioxidant MnTBAP, during CsA therapy, caused a reduction in SGVHD development as well as decreased colon mRNA levels for iNOS, CAMs and proinflammatory cytokines. These studies suggest a role for oxidative stress in the development of intestinal pathology associated with murine SGVHD. Research support: NIH Grant P01‐CA092372.