The Mechanism of Transfusion-Related Immunomodulation Is Related to the Transfusion of Dendritic Cells Expressing the CD200 (OX-2) Tolerance Signal and Alloantigen: Evidence from a Murine Tumor Model.
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AbstractBackground: The transfusion of blood products containing allogeneic leukocytes can alter recipient resistance to infection and stimulate the growth of some types of tumors in animal models of transfusion-induced tumor growth. Transfusion related immunomodulation (TRIM) represents a credible mechanism for the altered resistance to infection seen clinically, but cannot explain the growth of non-immunogenic tumors in syngeneic hosts seen regularly in the various transfusion-related animal models of tumor growth.Methods and Results: In this study the transfusion of 50–200 μL of unmodified anticoagulated allogeneic BALB/c (H-2d) mouse blood into C57B1/6 (H-2b) mice, four days before being intravenously injected with syngeneic (H-2b) FSL10 fibrosarcoma cells (1–2 x 106 cells per mouse) resulted in a significant increase in the number of pulmonary nodules observed at 3 weeks compared to that seen in control mice. The median number of pulmonary nodules increased in an allogeneic blood transfusion dose-dependent manner, as did the proportion of mice without pulmonary nodules. This tumor growth-promoting effect of the allogeneic blood transfusions required the presence in the transfused blood of allogeneic CD11c+ dendritic cells bearing the CD200 co-stimulatory tolerance signal. This tumor growth-promoting effect of allogeneic blood could be blocked by specific monoclonal antibodies to either CD11c or to CD200. CD200 receptor-mediated signaling alone, in the absence of alloantigen, failed to augment the number of TRIM-induced pulmonary tumor nodules. Physiological concentrations of TGFβ, but not IL-10, were shown to stimulate proliferation of FSL10 cells in vitro in these studies. In this context, it is known that CD200 together with alloantigens are known to stimulate development of suppressor cells acting via IL-10 and TGFβ in vivo. Allogeneic blood also caused a significant CD200-dependent accumulation of TGFβ+ suppressor cells in the spleen, 12 days after transfusion, when the spleen cells could be shown to adoptively transfer the TRIM effect to naive animals.Conclusions: These data support the hypothesis that allogeneic transfusions in an allogeneic blood transfusion mouse tumor model results in tumor growth promotion in recipient mice. This effect appears to result in both the induction of TGFβ-producing suppressor cells as well as requiring the transfusion of allogeneic CD11c+ dendritic cells, bearing both CD200 tolerance signaling molecules and alloantigens.
