Transplant immunobiology, inflammation and mechanisms of disease
New Co-Stimulation Molecules And Their Function In Vivo
The world is currently awash with costimulation molecules. Individual labs tout this or that molecule as being key to T cell activation under specific (often ludicrously specific) conditions, but none of these "insights" have yet led to actual therapeutic agents in clinical use. This reflects several factors. Drug companies make drugs and then try and find an application for them, ideally rheumatoid arthritis, multiple sclerosis, asthma or some other widespread disease involving long-term therapy, but certainly not any of the indications subject to the "too small a market (e.g. <$200 million dollars/year)" rule. Biologics are difficult and expensive to develop. Hence, the science underlying all the costimulation hype needs to examined critically if progress is to be achieved. Rather than adding more and more costimulation molecules to the list and thinking they are all equally important such that the Immunology Today-type diagrams in peoples' minds becomes more and more complicated, some reality testing is called for, and may thereby lead to new therapeutic approaches. Transplant models provide particularly advantageous systems to test the importance of such costimulation pathways using knockouts and blocking monoclonal antibodies and fusion proteins. We are currently investigating ICOS/B&RP-1; PD-1 and its ligands, PD-L1 and PD-L2; B7-H3; BTLA and B7-H4; and several TNF/TNF-R superfamily pathways, i.e. those molecules which constitute the "next wave" on which immunologic hopes, careers and dreams typically seem to be pinned upon but which in this case, as a bonus, may also be "true".
Chemokines/chemokine receptors in allograft rejection vs. tolerance
If all the world is a stage than an organ transplant is from an immunologic perspective a gothic masterpiece wherein every component of the immune system boils and pokes its way into the limelight at some point or another and the challenge is to make sense of it all. Chemokines are small molecular weight chemotactic cytokines which bind and signal via G protein-coupled seven-transmembrane receptors expressed by most cell types. Of special interest to immunologists are those chemokine receptors which mediate T cell recirculation as well as those which mediate attraction to sites of immune stimulation, such as an organ transplant. This field has its problems, not the least of which is its dreaded new nomenclature which has only served to decrease rather than improve communication. Suffice to say that despite there being over 45 chemokines and at least 18 chemokine receptors, with countless assertions of biologic redundancy and "promiscuous" binding (which sound interesting but isn't in this case), the development and testing of knockout mice and availability of neutralizing mAbs for use in wild-type controls has provided some sense of insight into how these pathways work in vivo. Of the various pathways involved in allograft responses, the most important seems to be CXCR3, which is expressed by NK cells and activated T cells, and has 3 ligands: IP-10, Mig and I-TAC. Blockade of CXCR3 has a particularly powerful effect in reducing host alloresponses. The second most important appears to be CCR5, whose ligands are many but include MIP-1a, MIP-1b and RANTES. We continue to investigate the importance of these and additional chemokine/chemokine receptor pathways in experimental and clinical studies.
Chatila WM, Criner GJ, Hancock WW, Akimova T, Moldover B, Chang JK, Cornwell W, Santerre M, Rogers TJ.: Blunted expression of miR-199a-5p in regulatory T cells of patients with chronic obstructive pulmonary disease compared to unaffected smokers. Clinical and Experimental Immunology Page: In press, April 2014.
Rowell E, Wang L, Chunder N, Hancock WW, Wells AD.
: Regulation of T cell differentiation and alloimmunity by the cyclin-dependent kinase inhibitor p18ink4c.
PLoS ONE 9: e91587, March 2014.
Wolf Joshua H, Bhatti Tricia R, Fouraschen Suomi, Chakravorty Shourjo, Wang Liqing, Kurian Sunil, Salomon Daniel, Olthoff Kim M, Levine Matthew H, Hancock Wayne W.: Heat shock protein-70 is required for optimal liver regeneration after partial hepatectomy in mice. Liver Transplantation Mar 2014.
Diamond Joshua M, Akimova Tatiana, Kazi Altaf, Shah Rupal J, Cantu Edward, Feng Rui, Levine Matthew H, Kawut Steven M, Meyer Nuala J, Lee James C, Hancock Wayne W, Aplenc Richard, Ware Lorraine B, Palmer Scott M, Bhorade Sangeeta, Lama Vibha N, Weinacker Ann, Orens Jonathan, Wille Keith, Crespo Maria, Lederer David J, Arcasoy Selim, Demissie Ejigayehu, Christie Jason D: Genetic Variation in Prostaglandin E2 Pathway is Associated with Primary Graft Dysfunction. American Journal of Respiratory and Critical Care Medicine Mar 2014.
Akimova T, Xiao H, Liu Y, Bhatti TR, Jiao J, Eruslanov E, Singhal S, Wang L, Han R, Zacharia K, Beier UH, Hancock WW.: Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells. Mucosal Immunology Page: doi: 10.1038/mi.2014.10, Feb 2014.
Hancock Wayne W: Effects of histone deacetylase inhibitors on alloresponses. Lancet Oncology 15(1): 10-1, Jan 2014.
Wang Liqing, Liu Yujie, Han Rongxiang, Beier Ulf H, Thomas Rajan M, Wells Andrew D, Hancock Wayne W: Mbd2 promotes Foxp3 demethylation and T-regulatory cell function. Molecular and Cellular Biology 33(20): 4106-15, Oct 2013.
Liu Yujie, Wang Liqing, Predina Jarrod, Han Rongxiang, Beier Ulf H, Wang Liang-Chuan S, Kapoor Veena, Bhatti Tricia R, Akimova Tatiana, Singhal Sunil, Brindle Paul K, Cole Philip A, Albelda Steven M, Hancock Wayne W: Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity. Nature Medicine 19(9): 1173-7, Sep 2013.
Wang L, Liu Y, Beier UH, Han R, Bhatti TR, Akimova T, Hancock WW.: Foxp3+ T regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity.
Blood In press, 2013.
Zheng Rena, Rebolledo-Jaramillo Boris, Zong Yiwei, Wang Liqing, Russo Pierre, Hancock Wayne, Stanger Ben Z, Hardison Ross C, Blobel Gerd A: Function of GATA Factors in the Adult Mouse Liver. PLoS One 8(12): e83723, 2013.
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Last updated: 03/11/2014
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