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Related Collections Immunobiology Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2002, Vol. 99, No. 4, pp. 1465-1473 TRANSPLANTATION Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses Dimitrios Tzachanis, Alla Berezovskaya, Lee M. Nadler, and Vassiliki A. Boussiotis From the Department of Adult Oncology, Dana Farber Cancer Institute, and the Division of Medical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Blockade of B7/CD28 costimulation allows human haploidentical bone marrow transplantation without graft-versus-host disease. This study shows that blockade of B7/CD28 in anergizing mixed lymphocyte reaction (MLR) cultures of peripheral blood mononuclear cells results in the generation of alternatively activated macrophages (AAM). In contrast, priming MLR cultures result in generation of classically activated macrophages (CAM). AAM had enhanced expression of CD14, major histocompatibility complex class II, and CD23; produced alternative macrophage activation-associated CC-chemokine 1 (AMAC-1) chemokine; and displayed increased phagocytotic activity but decreased ability for antigen presentation. Suppression subtractive hybridization revealed that although AAM had undergone terminal maturation and differentiation, they entered a distinct gene expression program as compared with CAM and selectively expressed 2-microglobulin, lysozyme, ferritin heavy and light chain, and the scavenger receptors macrophage mannose receptor and sortilin. Anergic T cells isolated from cultures that led to the development of AAM produced low amounts of interleukin-2 (IL-2), IL-4, and interferon-, but high amounts of IL-10. Addition of anti-IL-10 neutralizing monoclonal antibody in anergizing cultures reversed the functional characteristics of AAM, indicating that at least one mechanism involved in the generation of AAM was mediated by IL-10. Importantly, when added in MLR cultures, AAM suppressed T-cell responses. Therefore, besides direct inhibition of T-cell costimulation, blockade of B7/CD28 may facilitate induction of T-cell unresponsiveness by generating AAM. Because in healthy individuals, AAM are found in the placenta and lung, where they protect from unwanted immune reactivity, the results suggest that AAM may play a critical role in the induction of transplantation tolerance. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A.-S. Dugast, T. Haudebourg, F. Coulon, M. Heslan, F. Haspot, N. Poirier, R. Vuillefroy de Silly, C. Usal, H. Smit, B. Martinet, et al. 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