Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation.

IL-10 is a potent immunosuppressant which inhibits allo-antigen-specific T cell responses. In addition, IL-10 is a strong endogenous anti-inflammatory cytokine. To investigate the role of IL-10 in the induction of acute GVHD following allogeneic bone marrow transplantation (BMT) we performed a prospective study on spontaneous IL-10 production by peripheral blood mononuclear cells (PBMNC) in 84 patients admitted for allogeneic BMT.

Inflammatory reactions induced by pretransplant conditioning--an alternative target for modulation of acute GvHD and complications following allogeneic bone marrow transplantation?

Intensity of pretransplant conditioning has been closely correlated with regimen related toxicity in patients receiving allogeneic bone marrow transplantation (BMT). In this review, we summarize evidence for a direct link between inflammatory reactions induced by irradiation and cytotoxic treatment and occurrence of acute graft-versus-host disease (GvHD) as well as endothelial complications: In our studies, de novo release of TNFalpha during conditioning was associated with an increased risk of severe GvHD and mortality following BMT, whereas increased spontaneous production of IL-10, an endogenous TNF-antagonist, prior to conditioning protected from these complications. Immunogenetic differences in cytokine regulation and costimulation by endotoxin proved to be important cofactors determining the extent of inflammatory cytokine release in individual patients.

Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F).

Contribution of host-related cytokine release in the course of pretransplant conditioning to early tissue damage and induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) has been shown in experimental models. We performed a clinical phase I/II trial applying a monoclonal antibody neutralizing human tumor necrosis alpha (TNF alpha) during pretransplant conditioning as additional prophylaxis in high-risk patients admitted to allogeneic BMT; TNF alpha serum levels and clinical courses in 21 patients receiving anti-TNF alpha prophylaxis were compared with data from 22 historical controls. Absence of significant release of TNF alpha in the period of busulphan (BUS) treatment, but significant induction of TNF alpha by total body irradiation (TBI) and cyclophosphamide (CY) conditioning were correlated with significantly earlier onset of acute GVHD in patients receiving TBI/CY regimens as compared with BUS/CY-treated patients.

Ionizing radiation induces human intercellular adhesion molecule-1 in vitro.

Intercellular adhesion molecule-1 (ICAM-1) plays a central role in various inflammatory reactions and its expression is readily induced by inflammatory stimuli such as cytokines or ultraviolet irradiation. We have investigated the effect of ionizing radiation (IR) on human ICAM-1 expression in human cell lines and skin cultures. ICAM-1 mRNA levels in HL60, HaCaT, and HeLa cells were elevated at 3-6 h after irradiation and increased with doses from 10-40 Gy.

Low incidence of transplant-related complications in patients with chronic release of tumor necrosis factor-alpha before admission to bone marrow transplantation: a clinical correlate of cytokine desensitization?

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) released by activated macrophages, sequential serum samples of 120 patients undergoing bone marrow transplantation (BMT) were analyzed by enzyme-linked immunosorbent assay. De novo increases in serum TNF-alpha levels were correlated with the development of acute endothelial complications as well as acute graft-versus-host disease. In addition, the analysis of time courses revealed a different capacity of TNF-alpha regulation at various phases of BMT.