Daniel Jane-Wit, MD/PhD
Research & Publications
Biography
News
Research Summary
While recent advances have improved rates of early allograft loss, late allograft loss occurring >1 year post-transplantation remains medically untreatable and accounts for an annualized rate of graft loss of ~4%. Late allograft loss is most commonly attributed to chronic antibody-mediated rejection (CABMR), a condition characterized by vascular complications including complement activation and vasculopathy, i.e., development of vaso-occlusive lesions leading to ischemic complications.
Complement are a set of circulating immune proteins involved in host defense that critically mediate CABMR. Upon terminal activation, complement proteins self-assemble into transmembranous pores called membrane attack complexes (MAC). MAC insert into surfaces of endothelial cells (ECs), the cells that line blood vessels, to trigger inflammation. We used sera from allo-sensitized transplant candidates to model the effects of complement, and we discovered an endosome-based signaling mechanism activated by MAC that resulted in activation of at least three pro-inflammatory pathways, non-canonical NF-kB, NLRP3 inflammasomes, and canonical NF-kB in ECs. These pathways collectively activated a broad range of inflammatory molecules and potentiated the ability of ECs to activate alloimmune CD4+ T cells. Our laboratory has developed novel assays to explore this endosome-associated pathway in cultured human EC, in two humanized mouse models reproducing clinical features of CABMR, and in patient biospecimens. We believe this pathway is broadly relevant to many complement-mediated conditions and as such may represent an attractive therapeutic target.
Our current areas of research includes: 1) determining endosome-associated signaling components(s) required for complement to induce EC activation, and 2) identifying CD4+ T cell subset(s) that may be activated by MAC-bound ECs. We have a number of ongoing translational projects in each of these areas that are very exciting. Please contact me if you have an interest in any of the above.
Coauthors
Research Interests
Endothelium, Vascular; Transplantation Immunology; Heart Transplantation
Selected Publications
- ZFYVE21 is a Mediator of Non-Canonical Hedgehog Signaling Activating NLRP3 Inflammasomes in a Pathologic Subset of CD4+PD-1hi T CellsJiang B, Fang C, Soh C, Li X, Geirsson A, Tellides G, Pober J, Jane-Wit D. ZFYVE21 is a Mediator of Non-Canonical Hedgehog Signaling Activating NLRP3 Inflammasomes in a Pathologic Subset of CD4+PD-1hi T Cells The Journal Of Heart And Lung Transplantation 2021, 40: s136. DOI: 10.1016/j.healun.2021.01.422.
- ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomesFang C, Manes TD, Liu L, Liu K, Qin L, Li G, Tobiasova Z, Kirkiles-Smith NC, Patel M, Merola J, Fu W, Liu R, Xie C, Tietjen GT, Nigrovic PA, Tellides G, Pober JS, Jane-wit D. ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes Nature Communications 2019, 10: 2247. PMID: 31113953, PMCID: PMC6529429, DOI: 10.1038/s41467-019-10041-2.
- Complement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-γ–Primed Human EndotheliumXie CB, Qin L, Li G, Fang C, Kirkiles-Smith NC, Tellides G, Pober JS, Jane-Wit D. Complement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-γ–Primed Human Endothelium Circulation Research 2019, 124: 1747-1759. PMID: 31170059, PMCID: PMC6557295, DOI: 10.1161/circresaha.119.314845.
- Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomesJane-wit D, Surovtseva YV, Qin L, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles-Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomes Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 9686-9691. PMID: 26195760, PMCID: PMC4534258, DOI: 10.1073/pnas.1503535112.
- Abstract 417: Endosome-Based Activation of Non-Canonical NF-kB Signaling by Complement Membrane Attack ComplexesJane-wit D, Surovtseva Y, Qin L, Liu R, Clark P, Manes T, Wang C, Kashgarian M, Kirkiles-Smith N, Tellides G, Pober J. Abstract 417: Endosome-Based Activation of Non-Canonical NF-kB Signaling by Complement Membrane Attack Complexes Arteriosclerosis Thrombosis And Vascular Biology 2015, 35 DOI: 10.1161/atvb.35.suppl_1.417.
- Alloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-&kgr;B Signaling in Endothelial CellsJane-wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, Abrahimi P, Devalliere J, Moeckel G, Kulkarni S, Tellides G, Pober JS. Alloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-&kgr;B Signaling in Endothelial Cells Circulation 2013, 128: 2504-2516. PMID: 24045046, PMCID: PMC3885874, DOI: 10.1161/circulationaha.113.002972.
- IDENTIFICATION OF A NOVEL COMPLEMENT–INDUCED SIGNALING PATHWAY IN ENDOTHELIAL CELLS THAT IS IMPLICATED IN THE DEVELOPMENT OF CORONARY GRAFT VASCULOPATHYJane–Wit D, Pober J, Tellides G. IDENTIFICATION OF A NOVEL COMPLEMENT–INDUCED SIGNALING PATHWAY IN ENDOTHELIAL CELLS THAT IS IMPLICATED IN THE DEVELOPMENT OF CORONARY GRAFT VASCULOPATHY Journal Of The American College Of Cardiology 2013, 61: e2109. DOI: 10.1016/s0735-1097(13)62109-9.
- Autoimmune mediated regulation of ovarian tumor growthAltuntas C, Jaini R, Kesaraju P, Jane-wit D, Johnson J, Covey K, Flask C, Dutertre M, Picard J, Tuohy V. Autoimmune mediated regulation of ovarian tumor growth Gynecologic Oncology 2011, 124: 98-104. PMID: 22004903, PMCID: PMC3258506, DOI: 10.1016/j.ygyno.2011.09.023.
- An autoimmune-mediated strategy for prophylactic breast cancer vaccinationJaini R, Kesaraju P, Johnson J, Altuntas C, Jane-wit D, Tuohy V. An autoimmune-mediated strategy for prophylactic breast cancer vaccination Nature Medicine 2010, 16: 799-803. PMID: 20512124, PMCID: PMC3095829, DOI: 10.1038/nm.2161.
- Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated CardiomyopathyJane-wit D, Altuntas C, Monti J, Johnson J, Forsthuber T, Tuohy V. Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy American Journal Of Pathology 2007, 172: 11-21. PMID: 18063702, PMCID: PMC2189613, DOI: 10.2353/ajpath.2008.070324.
- β1-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte ApoptosisJane-wit D, Altuntas C, Johnson J, Yong S, Wickley P, Clark P, Wang Q, Popović Z, Penn M, Damron D, Perez D, Tuohy V. β1-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis Circulation 2007, 116: 399-410. PMID: 17620508, DOI: 10.1161/circulationaha.106.683193.