Immunology Graduate Group
Wayne W. Hancock, Ph.D.
Professor, Pathology and Laboratory Medicine
Address: 916E Abramson Research Center, Children's Hospital of Philadelphia
Office Phone: (215) 590-8709
Fax: (215) 590-7384
Email: whancock@mail.med.upenn.edu
Education:
FRCPA, Royal College of Pathologists of Australasia
Ph. D., Monash University (Australia)
M.B.B.S, Monash University
Research Interests
Transplant immunobiology, inflammation and mechanisms of disease
Research Summary
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.
Recent Publications
Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard CJ. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. Journal of Experimental Medicine 192, 2000, 1515-1519
Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Desai R, Hancock WW, Weiner HL, Selkoe DJ. Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Annals of the New York Academy of Sciences 920, 2000, 328-31
Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. Donor-derived IP-10 initiates development of acute allograft rejection. Journal of Experimental Medicine 193, 2001, 975-980
Csizmadia V, Gao W, Hancock SA, Rottman JB, Wu Z, Turka LA, Siebenlist U, Hancock WW.
Differential NF- B and I B gene expression during development of cardiac allograft rejection vs. CD154 monoclonal antibody-induced tolerance (Rapid Communication). Transplantation 71, 2001, 835-840
Özkaynak E, Gao W, Shemmeri N, Wang C, Gutierrez-Ramos JC, Amaral J, Qin S, Rottman JB, Coyle AJ, Hancock WW. Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection. Nature Immunology 2, 2001, 591-596
Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. Journal of Immunology 167, 2001, 2887-2894
Haskell CA, Hancock WW, Salant DJ, Gao W, Csizmadia V, Peters W, Faia K, Fituri O, Rottman JB, Charo IF. Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection. Journal of Clinical Investigation 108, 2001, 679-688
Emmanuilidis K, Weighardt H, Maier S, Gerauer K, Fleischmann T, Zheng XX, Hancock WW, Holzmann B, Heidecke CD. Critical role of Kupffer cell-derived IL-10 for host defense in septic peritonitis. Journal of Immunology 167, 2001, 3919-3927
Gao W, Faia KL, Csizmadia V, Smiley ST, Soler D, King JA, Danoff TM, Hancock WW. Beneficial effects of targeting CCR5 in allograft recipients (Rapid Communication). Transplantation 72, 2001, 1199-1205
Pratschke H, Wilhelm MJ, Laskowski I, Kusaka M, Beato F, Tullius SG, Neuhaus P, Hancock WW, Tilney NL. Influence of donor brain death on chronic rejection of renal transplants in rats. Journal of the American Society of Nephrology 12, 2001, 2474-2481
Melter M, Exeni A, Reinders MEJ, Fang JC, McMahon G, Ganz P, Hancock WW*, Briscoe DM* Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection. Circulation 104, 2001, 2558-2564
Laskowski IA, Pratschke J, Wilhelm MJ, Dong VM, Beato F, Taal M, Gasser M, Hancock WW, Sayegh MH, Tilney NL. Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats. American Journal of Kidney Diseases 13, 2002, 519-527
Hancock WW. Chemokines and transplant immunobiology. Journal of the American Society of Nephrology 13, 2002, 821-824
Ye Q, Fraser CC, Gao W, Wang L, Busfield SJ, Wang C, Qiu Y, Coyle AJ, Gutierrez-Ramos JC, Hancock WW. Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival. Journal of Experimental Medicine 195, 2002, 795-800
Hancock WW, Gao W, Shemmeri N, Shen XD, Gao F, Busuttil RW, Zhai Y, Kupiec-Weglinski JW. Immunopathogenesis of accelerated allograft rejection in sensitized recipients: Humoral and non-humoral mechanisms. Transplantation 73, 2002, 1392-1997
Laskowski IA, Pratschke J, Wilhelm MJ, Gasser M, Paz D, Hancock WW, Tilney NL. Early and late injury to renal transplants from non-heart-beating donors. Transplantation 73, 2002, 1468-1473
Gasser M, Waaga AM, Kist-Van Holthe JE, Lenhard SM, Laskowski I, Shaw GD, Hancock WW, Tilney NL. Normalization of brain death-induced injury to rat renal allografts by recombinant soluble P-selectin glycoprotein ligand. Journal of the American Society of Nephrology 13, 2002, 1937-1945
Yang H, Thomas D, Boffa DJ, Ding R, Li B, Muthukumar T, Sharma VK, Lagman M, Luo GX, Kapur S, Liou HC, Hancock WW, Suthanthiran M. Enforced c-Rel deficiency prolongs survival of islet allografts. Transplantation 74, 2002, 291-298
Kusaka M, Mackenzie HS, Ziai F, Hancock WW, Tilney NL. Recipient hypertension potentiates chronic functional and structural injury of rat renal allografts. Transplantation 74, 2002, 307-314
Hancock WW. Chemokines and chemokine receptors as potential targets for immunosuppression.
Transplantation and Immunology Letter 18, 2002, 4-13
Özkaynak E, Wang L, Goodearl A, McDonald K, Qin S, O'Keefe T, Duong T, Smith T, Steininger R, Gutierrez-Ramos JC, Rottman JB, Coyle AJ, Hancock WW. Programmed death-1 targeting can promote allograft survival. Journal of Immunology 169, 2002, 6546-6553
Thomas D, Yang H, Boffa DJ, Ding R, Sharma VK, Lagman M, Li B, Hering B, Mohanakumar T, Lakey J, Kapur S, Hancock WW, Suthanthiran M. Proapoptotic Bax is hyperexpressed in isolated human islets compared with antiapoptotic Bcl-2. Transplantation 74, 2002, 1489-1496
Hancock WW, Wang L, Ye Q. Chemokine-directed dendritic cell trafficking in allograft rejection.
Current Opinion in Organ Transplantation 8, 2003, 35-39
Sayegh MH, Wu Z, Hancock WW, Langmuir PB, Mata M, Sandner S, Kishimoto K, Sho M, Palmer E, Mitchell RN, Turka LA. Allograft rejection in a new allospecific CD4+ TCR transgenic mouse. American Journal of Transplantation 3, 2003, 381-389
Araujo JA, Meng L, Tward AD, Hancock WW, Zhai Y, Lee A, Ishikawa K, Iyer S, Buelow R, Busuttil RW, Shih DM, Lusis AJ, Kupiec-Weglinski JW. Systemic rather than local heme oxygenase-1 overexpression improves cardiac allograft outcomes in a new transgenic mouse. Journal of Immunology 171, 2003, 1572-1580
Akalin E, Dikman S, Murphy B, Bromberg JS, Hancock WW. Glomerular infiltration by CXCR3+ ICOS+ activated T cells in chronic allograft nephropathy with transplant glomerulopathy. American Journal of Transplantation 3, 2003, 1116-1120
Hancock WW, Tsai TL, Madaio M, Gasser DL. Multiple autoimmune pathways in kd/kd mice. Journal of Immunology 171, 2003, 2778-2781
Hancock WW, Wang L, Ye Q, Han R, Lee I. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Current Opinion in Immunology 15, 2003, 479-486
Kobayashi T, Walsh PT, Walsh MC, Speirs KM, Chiffoleau E, King CG, Hancock WW, Caamano JH, Hunter CA, Scott P, Turka LA, Choi Y. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19, 2003, 353-363
Chen D, Ding Y, Zhang N, Schröppel B, Fu S, Zang W, Zhang H, Hancock WW, Bromberg JS.
Viral IL-10 gene transfer inhibits the expression of multiple chemokine and chemokine receptor genes induced by inflammatory or adaptive immune stimuli. American Journal of Transplantation (In press)
Chiffoleau E, Kobayashi T, Walsh MC, King CG, Walsh PT, Hancock WW, Choi Y, Turka LA. TRAF6 deletion during hematopoiesis causes myeloid expansion and Th2 polarized inflammatory disease. Journal of Immunology (In press)
Lee I, Wang L, Wells AD, Ye Q, Han R, Dorf ME, Kuziel WA, Rollins BJ, Chen L, Hancock WW.
Blocking the MCP-1/CCR2 chemokine pathway induces permanent survival of islet allografts through a PD-L1-dependent mechanism. Journal of Immunology (In press)