BackgroundThe mutant chondrodysplasia (cho) is a cartilage‐targeting disorder in C57BL mice that results in dwarfing and other malformations stemming from this collagenopathy. Clarke Fraser made the discovery of the mutation accidentally in the early 1960s during the thalidomide tragedy.MethodsFor this review we identified key research on cho as since its discovery. Relevant data were compiled to make a comprehensive review that details discoveries associated with the cho mutation, that describes the associated phenotypes and molecular mechanisms, and that provides a discussion surrounding its current clinical relevance.ResultsMechanistically, cho acts by hindering chondrogenesis and endochondral bone formation. The phenotype results from a 1‐nt deletion in the gene encoding the alpha 1 chain of type XI collagen. For more than half a century, researchers have studied the pathogenesis of the cho mutation in relation to a variety of mouse models of human birth defects and disease. These studies have resulted in several discoveries linking cho with such human disorders as dwarfism, tracheal stenosis, cleft palate, pulmonary hypoplasia, and osteoarthritis (OA).ConclusionThe study of cho has led to numerous advances in understanding human birth defects, congenital disorders, and adult human disease. The most recent studies have suggested a role for the TGF‐Beta, HtrA1, Ddr2, and Mmp‐13 pathway in the degradation of articular cartilage and the development of OA in cho/+ mice. We have shown that the anti‐hypertension drug Losartan is a TGF‐Beta blocker that could be used to treat OA in Stickler syndrome, and thereby rescue the WT phenotype.

01 Jan 2007·Transplantation ProceedingsQ4 · MEDICINE

Cross-Tolerance of Recipient-Derived Transforming Growth Factor-Beta Dendritic Cells

Q4 · MEDICINE

Article

Author: L. Lu ; S. Qian ; M.-M. Tiao ; C.-L. Chen ; L.-T. Huang ; C.-D. Liang ; J.J. Fung ; R. Tao

Administration of donor-derived immature dendritic cells (DC) treated with transforming growth factor-beta (TGF-beta) to prevent allograft rejection is not applicable for clinical use. We therefore attempted to explore the use of recipient-derived DC pulsed with donor antigens via the indirect pathway (cross-priming). DC were propagated from C3H (H2(k)) bone marrow (BM) using granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). TGF-beta (0.2 ng/mL) was added at the initiation of culture. The resultant TGF-beta DC were pulsed with B10 (H2(b)) splenocyte lysate. Expression of major histocompatibility complex (MHC) class I and II was not affected, while CD40, CD80, and CD86 costimulatory molecules on DC were significantly inhibited by treatment with TGF-beta. C3H DC pulsed with B10 antigens stimulated a proliferative response in C3H T cells which was inhibited when DC were treated with TGF-beta, and the cytotoxic T-lymphocyte (CTL) activity was also inhibited. This observation correlated with reduced interferon-gamma (IFN-gamma) and increased IL-10 production. A single injection of TGF-beta DC prolonged allograft survival (median survival time [MST] 18 days vs 10 days in no-DC treatment control; P < .05). These data indicated that an approach utilizing recipient DC as a "vaccine" strategy is possible.

01 Apr 2005·CytokineQ3 · MEDICINE

Roles of reactive nitrogen intermediates and transforming growth factor-β produced by immunosuppressive macrophages in the expression of suppressor activity against T cell proliferation induced by TCR stimulation

Q3 · MEDICINE

Article

Author: Shanshan Cai ; Haruaki Tomioka ; Toshiaki Shimizu

The suppressor activity of splenic macrophages induced by Mycobacterium intracellulare infection (MI-M phi s) against T cell concanavalin A (Con A) mitogenesis is mediated by MI-M phi's mediators, such as reactive nitrogen intermediates (RNIs), phosphatidylserine, free fatty acids, prostaglandin E(2) and to a minor extent TGF-beta. Here, we have compared the roles of RNIs and TGF-beta in the expression of MI-M phi's suppressor activity against Con A mitogenesis and anti-CD3 monoclonal antibody (mAb)- and anti-CD28 mAb-induced mitogenesis (TCR signal-induced mitogenesis) of the target T cells, and have found the following. First, N(G)-monomethyl-L-arginine (NMMA) inhibited MI-M phi's suppressor activity against TCR signal-induced mitogenesis as well as Con A mitogenesis. Second, anti-TGF-beta mAb weakly restored the MI-M phi-mediated suppression only in the case of Con A mitogenesis, under limited conditions, such as very low cell densities of MI-M phi s. Third, the blocking effects of NMMA plus anti-TGF-beta mAb were somewhat more prominent in the case of Con A mitogenesis than in the case of TCR signal-induced mitogenesis. Fourth, Con A- or TCR signal-stimulated MI-M phi s secreted significant amounts of the latent TGF-beta but not the active one. These findings indicate that RNIs, but not TGF-beta, play important roles in the MI-M phi-mediated suppression of TCR signal-induced mitogenesis, as well as Con A mitogenesis, of the target T cells.

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