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These data indicate that one mechanism by which gliomas cause immunosuppressive effects is the induction of monocytes to release soluble factors that promote activated T-cell apoptosis. The loss of activated T cells leads to T lymphopenia and contributes to the deficiencies in cell-mediated immunity that have been observed during testing of glioma patients' immune function.

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...

Patients with gliomas exhibit deficient in vitro and in vivo T cell immune activity, and human glioblastoma culture supernatants (GCS) inhibit in vitro T lymphocyte responses. Because APC are essential for initiating and regulating T cell responses, we investigated whether GCS would affect cytokines produced by monocytes and T cells from healthy donors of PBMC. Incubation of PBMC with GCS decreased production of IL-12, IFN-γ, and TNF-α, and increased production of IL-6 and IL-10. The GCS-induced changes in IL-12 and IL-10 occurred in monocytes, and involved changes in IL-12 p40 and IL-10 mRNA expression. Incubation with GCS also resulted in reduced expression of MHC class II and of CD80/86 costimulatory molecules on monocytes. The immunosuppressive effects were not the result of IL-6 or TGF-β1 that was detected in GCS. However, it was due to a factor(s) that is resistant to pH extremes, differentially susceptible to temperature, susceptible to trypsin, and has a minimum molecular mass of 40 kDa. Our findings show that glioblastoma-generated factors that are known to suppress T cell responses alter the cytokine profiles of monocytic APC that, in turn, inhibit T cell function. This model indicates that monocytes can serve as an intermediate between tumor-generated immune-suppressive factors and the T cell responses that are suppressed in gliomas.