transforming-growth-factor-beta and Transfusion-Reaction

Transforming growth factor-beta1 (TGF-beta1) is released during the storage of blood components, particularly platelet concentrates, and transfusion recipients are exposed to high levels of TGF-beta1. Because TGF-beta1 is one of the most potent immunosuppressive cytokines known, understanding the immunobiologic functions of TGF-beta1 may be relevant for understanding the immunobiologic effects of transfusion. Our laboratory studies the biologic effects of TGF-beta1 in the immune system. Mice deficient in TGF-beta1 spontaneously develop autoimmunity, confirming the important role of this cytokinean an immune regulator. A few years ago, my laboratory made the observation that genetic background strongly affects the phenotype of TGF-beta1-/- mice. TGF-beta1-/- mice on the BALB/c background rapidly develop an aggressive T-cell-mediated hepatitis, whereas TGF-beta1-/- mice on the 129/CF-1 background do not. In this review, I summarize findings published or in press from our laboratory on disease pathogenesis in TGF-beta1-/- mice and then discuss some of the exciting (as-yet-unpublished) directions our laboratory is currently taking.

Topics: Animals; Autoimmune Diseases; Humans; Liver; Liver Diseases; Mice; Species Specificity; Th1 Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transfusion Reaction

Topics: Apoptosis; Humans; Immunosuppression Therapy; Macrophages; Phagocytosis; Phosphatidylserines; Transforming Growth Factor beta; Transfusion Reaction

The transfusion of allogeneic blood products containing white cells (WBCs) has been reported to reduce resistance to infection, stimulate the growth of some types of tumors in animal models, and prevent abortion of allogeneic embryos in the CBAxDBA/2 murine model.. In this study, the issue explored was whether allogeneic BALB/c whole blood given to C57Bl/6 mice by tail vein after injection of syngeneic FSL-10 fibrosarcoma cells increased the number of lung nodules enumerated on Day 21. The effect on the tumor growth-promoting effect produced by allogeneic BALB/c whole blood was then examined by exposure of the allogeneic BALB/c blood to various monoclonal antibodies (MoAbs). The antibodies added to the BALB/c blood included anti-murine CD200 antibodies, anti-lymphoid dendritic cell (DC) antibodies (DEC205), or anti-myeloid DC (anti-CD11c) antibodies.. The tumor growth-promoting effect of the allogeneic BALB/c blood was abrogated by the addition to the BALB/c blood of MoAb either to myeloid DCs (anti-CD11c) or to the CD200 tolerance signaling molecule, but not by adding MoAb to lymphoid DCs (DEC205). BALB/c blood also was shown to increase the percentage of transforming growth factor (TGF)-beta+ splenocytes detected in recipient mice, on Day 12 after transfusion. This effect was abrogated by adding anti-CD200 antibody to the BALB/c donor blood. Moreover, physiologic concentrations of TGF-beta, but not interleukin-10, were shown to stimulate, in cell culture experiments, the proliferation of syngeneic FSL-10 sarcoma cells.. These data support the hypothesis that the mechanism of the tumor growth-promoting effect of allogeneic blood is mediated by a highly potent population of peripheral blood DCs expressing the CD200 tolerance signaling molecule. These data also indicate that tumor cell growth can be mediated by the stimulation of TGF-beta-producing cells and that TGF-beta may act by tumor cell growth stimulation, rather than by host immunosuppression.

Topics: Animals; Antigens, CD; CD11c Antigen; Dendritic Cells; Female; Fibrosarcoma; Immune Tolerance; Immunologic Factors; Isoantigens; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Transplantation; Signal Transduction; Spleen; Transforming Growth Factor beta; Transfusion Reaction

Topics: Activin Receptors, Type I; Animals; Apoptosis; Bone Marrow Transplantation; Enzyme Induction; Humans; Immunosuppression Therapy; Jurkat Cells; Macrophage Activation; Macrophages; Membrane Lipids; Mice; Models, Biological; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phagocytosis; Phosphatidylserines; Pneumonia; Protein Serine-Threonine Kinases; Radiation Chimera; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Respiratory Burst; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transfusion Reaction

Regular blood transfusions from infancy until adulthood in beta-thalassaemia major patients have substituted severe bone deformities with less marked skeletal lesions as osteoporosis. Osteoporosis is characterized by low bone mass and disruption of bone architecture, resulting in reduced bone strength and increased risk of fractures. Genetic factors have an important role in determining bone mineral density (BMD). We have investigated the possible association between BMD and two polymorphisms in 135 beta-thalassaemic patients: (i) a substitution G-->Tau in a regulatory region of the COLIA1 gene encoding for the major protein of bone (type 1 collagen), and (ii) a one-base deletion in intron 4 (713-8del C) of transforming growth factor beta 1 (TGF-beta1) gene. We have found a remarkable incidence (90%) of osteopenia and osteoporosis among regularly transfused patients. Bone mass was lower in men than in women (P = 0.0023), with a more prevalent osteopenia/osteoporosis of the spine in men than in women (P = 0. 001). The sample was stratified on the basis of BMD expressed as Z-score, i.e. normal, osteopenic and osteoporotic patients, and genotype frequencies of each group were evaluated. TGF-beta1 polymorphism failed to demonstrate a statistical difference in BMD groups. However, subjects with heterozygous or homozygous polymorphism of the COLIA1 gene showed a lower BMD than subjects without the sequence variation (P = 0.012). The differences among genotypes were still present when the BMD was analysed as adjusted Z-score and when men and women were analysed separately (P = 0.022 and 0.004 respectively), with men more severely affected. Analysis of COLIA1 polymorphism could help to identify those thalassaemic patients at risk of osteoporosis and fractures.

Topics: Adult; Analysis of Variance; beta-Thalassemia; Bone Density; Collagen; Female; Gene Deletion; Genotype; Humans; Male; Osteoporosis; Polymorphism, Genetic; Regression Analysis; Transforming Growth Factor beta; Transfusion Reaction