Summary:Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST Ͼ80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice. Keywords: syngeneic bone marrow transplantation; cyclosporin A; graft-versus-host disease; graft-versus-tumor Bone marrow transplantation (BMT) has been used as a first-line therapy for many patients with leukemia or lymphoma. 1,2 A major cause of morbidity and mortality following allogeneic BMT is graft-versus-host disease (GVHD), the development of which correlates with the presence of alloreactive T cells present in the donor cell inoculum. [1][2][3][4][5] Such cells initiate a multifactorial set of specific and nonspecific immune responses which result in the induction of the two forms of GVHD: acute and chronic. It has been shown in animal models 6 and in retrospective analyses of clinical studies of BMT for leukemias and lymphomas, that the development of GVHD following allogeneic BMT may be beneficial and correlate with a graftversus-leukemia (GVL) response. 7,8 Allogeneic BMT recipients who develop acute or chronic GVHD have lower relapse rates than patients transplanted with autologous or syngeneic BM. 9,10 Furthermore, when patients undergoing allogeneic transplants are given T cell-depleted BM to eliminate GVHD, increased relapse rates occur, suggesting that T cells present in the donor graft are necessary for inhibition of leukemic relapse. 11 Cytotoxic T lymphocytes (CTL), 12 lymphokine-activated killer cells, 13 and natural killer cells (NK) 14 are all thought to participate in the GVL process. Recently, much effort has been expended to discriminate beneficial GVL responses from the harmful GVHD effector mechanisms. In murine models of GVHD, it has been possible to separate GVHD immune mechanisms from GVL responses. 7 However, such findings have not yet been extrapolated to man.Interestingly, rodents treated with the immun...

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...