Description of Research Expertise

Research Interests

Transplant immunobiology, inflammation and mechanisms of disease, Treg cells, cancer immunology, therapeutics

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.

See: http://www.hancocklab.net

Selected Publications

Concors SJ, Hernandez PT, O’Brien C, DePaolo J, Murken DR, Aufhauser DD, Wang Z, Xiong Y, Krumeich L, Ge G, Beier UH, Bhatti TR, Kozikowski AP, Avelar L, Kurz T, Hancock WW, Levine MH.: Differential effects of HDAC6 inhibition versus knockout during hepatic ischemia reperfusion injury highlight importance of HDAC6 C-terminal zinc-finger ubiquitin-binding domain. Transplantation : In press,2024.

Akimova T, Wang L, Bartosh Z, Christensen L, Eruslanov E, Singhal S, Aishwarya V, Hancock WW.: Antisense targeting of FOXP3+ Tregs to boost anti-tumor immunity. Frontiers in Immunology 15 : 1426657,2024.

Christensen LM, Akimova T, Wang L, Han R, Samanta A, Di Giorgio E, Hancock WW.: T-regulatory cells require Sin3a for stable expression of Foxp3. Frontiers in Immunology 15 : 1444937,2024.

Thomas RM, Pahl MC, Wang L, Grant SFA, Hancock WW, Wells AD.: Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function. eLife : RP91392,2024.

Cravedi P, Riella LV, Ford M, Valujskikh A, Menon MC, Kirk AD, Alegre ML, Feng S, Kehn P, Najafian N, Hancock W, Heeger PS, Maltzman J, Mannon RB, Nadig S, Odim J, Turnquist H, Shaw J, West L, Luo X, Chong A, Bromberg J, on behalf of the AST COTS MOuse MOdels in Transplantation (MOMOT) work group.: Advancing mouse models for transplantation research. American Journal of Transplantation : https://doi.org/10.1016/j.ajt.2024.01.006,2024.

Patterson KC, Miller WT, Hancock WW, Akimova T.: FOXP3+ regulatory T cells are associated with the severity and prognosis of sarcoidosis. Frontiers in Immunology 14 : 1301991,2023.

Lax E, Do Carmo S, Enuka Y, Sapozhnikov DM, Welikovitch LA, Mahmood N, Rabbani SA, Wang L, Britt JP, Hancock WW, Yarden Y, Szyf M.: Methyl-CpG binding domain 2 (Mbd2) is an epigenetic regulator of autism-risk genes and cognition. Translational Psychiatry 13 : 259,2023.

Hernandez P, O’Brien C, Concors SJ, Wang Z, Ge G, Hancock WW, Levine MH.: The selective estrogen receptor modulator, Raloxifene, is protective against renal ischemia reperfusion injury. Transplantation 106 : 2166-2171,2022.

Graham ML, Ramachandran S, Singh A, Moore MEG, Flanagan EB, Azimzadeh A, Burlak C, Mueller KR, Martins K, Anazawa T, Balamurugan AN, Bansal-Pakala P, Murtaugh MP, O’Brien TD, Papas KK, Spizzo T, Schuurman HJ, Hancock WW, Hering BJ.: Clinically available immunosuppression with tacrolimus combined with basiliximab, rapamycin and CTLA4Ig averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques. American Journal of Transplantation 22 : 745-760,2022.

Graham ML, Ramachandran S, Singh A, Moore MEG, Flanagan EB, Azimzadeh A, Burlak C, Mueller KR, Martins K, Anazawa T, Balamurugan AN, Bansal-Pakala P, Murtaugh MP, O’Brien TD, Papas KK, Spizzo T, Schuurman HJ, Hancock WW, Hering BJ.: Clinically available immunosuppression with tacrolimus combined with basiliximab, rapamycin and CTLA4Ig averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques. American Journal of Transplantation 22 : 745-760,2022.

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Academic Contact Information

916B Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104-4318
Phone: 215-590-8709