Biochemistry; Biology; Biomedical Engineering; Immunogenetics
Rheumatic Diseases Research Core
Skin Diseases Research Center, Yale
WHRY Pilot Project Program Investigators
To characterize the development and function of regulatory T cells and characterize mechanisms that affect cancer, autoimmunity, inflammation, transplantation and recruitment into vascular sites.
Extensive Research Description
research goals of the lab are to characterize the development and function of
regulatory T cells and characterize mechanisms that affect autoimmunity,
inflammation, transplantation and recruitment into vascular sites. Both mouse and human responses are
studied in vitro and in vivo which includes the development and use of
humanized mice. In addition, our
experience with synthetic microvessels has lead to a translational project to
revascularize islets to treat type I diabetes.
Specific accomplishments in the last year:
- PPARs: Peroxysome proliferated activated receptors (PPARs) represent a group of transcription factors that are critical in regulating glucose and lipid metabolism. Ligands of PPARg inhibit metabolically induced arteriosclerosis and also prevent the development of inflammatory disorders in several experimental mouse models including EAE, asthma, rheumatic arthritis and sepsis. The role of PPARg in graft arteriosclerosis (GA) has not been characterized. We therefore tested the in vivo effects of administration of the endogenously occurring ligand, 15 deoxy-prostaglandin-J2 (15-d-PGJ2), and ciglitazone and pioglitazone on vascular remodeling of human artery induced by alloreactive PBMC and the IFN-g model. The data indicate that 15-d-PGJ2 and pioglitazone significantly inhibit human GA in our in vivo human arterial graft model in immunodeficient mice. These effects appear specific because they are reversed by treatment with an antagonist, GW9662. Preliminary results suggest that it is possible to reverse disease once it is established for 3 weeks in this model.
- Microorgan Islet Grafts: The goal of this project is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. Casting the islets together with EC in collagen gels effectively revascularizes the islets in SCID/bg mice. Indeed, our pilot data indicate that these human islet-EC microorgans secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests. We are characterizing the structure/function properties of these microorgans in detail, including the microvessel structure and the stability of the microvessels with time. During the last year we (with Serge Kobsa and M. Saltzman) are characterizing new nanospheres that have a greater capacity to secrete factors for longer periods of time. We have shown that Hepatocyte Growth Factor (HGF) has significant anti-apoptotic activity on islets in vitro and hope to evaluate this with the new delivery systems in vivo. Inflammation and Colon Cancer: The APC/Min mouse is a highly studied model of intestinal tumorigenesis. During the last year we have shown that APC/Min mice that are deficient in the proinflammatory cytokine IL-17A have a 90% reduction in small intestinal polyps. We hope to define both the source of the IL-17A that is critical as well as the cell type that is the target of this cytokine.
A humanized mouse model of autoimmune insulitis.
Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL. A humanized mouse model of autoimmune insulitis. Diabetes 2014, 63:1712-24.
Interplay between DNA repair and inflammation, and the link to cancer.
Kidane D, Chae WJ, Czochor J, Eckert KA, Glazer PM, Bothwell AL, Sweasy JB. Interplay between DNA repair and inflammation, and the link to cancer. Critical Reviews In Biochemistry And Molecular Biology 2014, 49:116-39.
- The Wnt antagonist Dickkopf-1 promotes pathological type 2 cell-mediated inflammation. Immunity 44: 246-258.
PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation.
Park HJ, Kim DH, Choi JY, Kim WJ, Kim JY, Senejani AG, Hwang SS, Kim LK, Tobiasova Z, Lee GR, Craft J, Bothwell AL, Choi JM. PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PloS One 2014, 9:e99127.
- Sex-based selectivity of PPARγ regulation in Th1, Th2, and Th17 differentiation. Int. J. Mol..Sci., 17:1347-1357; doi:10.3390/ijms17081347
Mutation of POLB causes lupus in mice.
Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB. Mutation of POLB causes lupus in mice. Cell Reports 2014, 6:1-8.
Full List of PubMed Publications
- Moon JS, Mun CH, Kim JH, Cho JY, Park SD, Park TY, Shin JS, Ho CC, Park YB, Ghosh S, Bothwell ALM, Lee SW, Lee SK: Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. Kidney Int. 2018 May; 2018 Mar 2. PMID: 29409726
- Xiao Q, Wu J, Wang WJ, Chen S, Zheng Y, Yu X, Meeth K, Sahraei M, Bothwell ALM, Chen L, Bosenberg M, Chen J, Sexl V, Sun L, Li L, Tang W, Wu D: DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med. 2018 Mar; 2018 Feb 12. PMID: 29431745
- Chae WJ, Bothwell ALM: Therapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside. Front Immunol. 2018; 2018 Feb 16. PMID: 29503652
- Chae WJ, Park JH, Henegariu O, Yilmaz S, Hao L, Bothwell ALM: Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis. Immunology. 2017 Oct; 2017 Jun 27. PMID: 28556921
- Jayakumar A, Bothwell ALM: Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response. Neoplasia. 2017 Aug; 2017 Jun 24. PMID: 28654863
- Chae WJ, Bothwell AL: Snapshots of CD4+ T cell plasticity in the pathogenesis of allergic asthma. J Thorac Dis. 2016 Sep. PMID: 27747048
- Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM: Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation. Int J Mol Sci. 2016 Aug 18; 2016 Aug 18. PMID: 27548145
- Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM: Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen. Sci Rep. 2016 Jun 23; 2016 Jun 23. PMID: 27335315
- Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D, Bothwell AL: The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity. 2016 Feb 16; 2016 Feb 9. PMID: 26872695
- Abrahimi P, Qin L, Chang WG, Bothwell AL, Tellides G, Saltzman WM, Pober JS: Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight. 2016; 2016 Jan 21. PMID: 26900601
- Lim S, Kim WJ, Kim YH, Lee S, Koo JH, Lee JA, Yoon H, Kim DH, Park HJ, Kim HM, Lee HG, Yun Kim J, Lee JU, Hun Shin J, Kyun Kim L, Doh J, Kim H, Lee SK, Bothwell AL, Suh M, Choi JM: dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. Nat Commun. 2015 Sep 15; 2015 Sep 15. PMID: 26372309
- Chae WJ, Bothwell AL: Spontaneous Intestinal Tumorigenesis in Apc (/Min+) Mice Requires Altered T Cell Development with IL-17A. J Immunol Res. 2015; 2015 Jun 3. PMID: 26146642
- Park TY, Park SD, Cho JY, Moon JS, Kim NY, Park K, Seong RH, Lee SW, Morio T, Bothwell AL, Lee SK: RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. Proc Natl Acad Sci U S A. 2014 Dec 30; 2014 Dec 19. PMID: 25527718
- Ehrlich A, Castilho TM, Goldsmith-Pestana K, Chae WJ, Bothwell AL, Sparwasser T, McMahon-Pratt D: The immunotherapeutic role of regulatory T cells in Leishmania (Viannia) panamensis infection. J Immunol. 2014 Sep 15; 2014 Aug 6. PMID: 25098291
- Park JH, Ko JS, Shin Y, Cho JY, Oh HA, Bothwell AL, Lee SK: Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells. Biochem Biophys Res Commun. 2014 Aug 15; 2014 Jul 17. PMID: 25044110
- Park HJ, Kim DH, Choi JY, Kim WJ, Kim JY, Senejani AG, Hwang SS, Kim LK, Tobiasova Z, Lee GR, Craft J, Bothwell AL, Choi JM: PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PLoS One. 2014; 2014 Jun 12. PMID: 24921943
- Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL: A humanized mouse model of autoimmune insulitis. Diabetes. 2014 May; 2014 Jan 29. PMID: 24478396
- Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB: Mutation of POLB causes lupus in mice. Cell Rep. 2014 Jan 16; 2014 Jan 2. PMID: 24388753
- Kobsa S, Kristofik NJ, Sawyer AJ, Bothwell AL, Kyriakides TR, Saltzman WM: An electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness wounds. Biomaterials. 2013 May; 2013 Feb 27. PMID: 23453058
- Yi T, Fogal B, Hao Z, Tobiasova Z, Wang C, Rao DA, Al-Lamki RS, Kirkiles-Smith NC, Kulkarni S, Bradley JR, Bothwell AL, Sessa WC, Tellides G, Pober JS: Reperfusion injury intensifies the adaptive human T cell alloresponse in a human-mouse chimeric artery model. Arterioscler Thromb Vasc Biol. 2012 Feb; 2011 Nov 3. PMID: 22053072
- Chae WJ, Bothwell AL: IL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice. Biochem Biophys Res Commun. 2011 Oct 14; 2011 Sep 12. PMID: 21939640
- Tobiasova Z, Zhang L, Yi T, Qin L, Manes TD, Kulkarni S, Lorber MI, Rodriguez FC, Choi JM, Tellides G, Pober JS, Kawikova I, Bothwell AL: Peroxisome proliferator-activated receptor-γ agonists prevent in vivo remodeling of human artery induced by alloreactive T cells. Circulation. 2011 Jul 12; 2011 Jun 20. PMID: 21690493
- Morer A, Chae W, Henegariu O, Bothwell AL, Leckman JF, Kawikova I: Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases. Brain Behav Immun. 2010 Oct; 2010 Mar 1. PMID: 20193755
- Kawikova I, Grady BP, Tobiasova Z, Zhang Y, Vojdani A, Katsovich L, Richmand BJ, Park TW, Bothwell AL, Leckman JF: Children with Tourette's syndrome may suffer immunoglobulin A dysgammaglobulinemia: preliminary report. Biol Psychiatry. 2010 Apr 1; 2009 Dec 14. PMID: 20006327
- Harding MJ, Lepus CM, Gibson TF, Shepherd BR, Gerber SA, Graham M, Paturzo FX, Rahner C, Madri JA, Bothwell AL, Lindenbach BD, Pober JS: An implantable vascularized protein gel construct that supports human fetal hepatoblast survival and infection by hepatitis C virus in mice. PLoS One. 2010 Apr 1; 2010 Apr 1. PMID: 20376322
- Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL: Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A. 2010 Mar 23; 2010 Mar 8. PMID: 20212110
- Chen W, Begum S, Opare-Addo L, Garyu J, Gibson TF, Bothwell AL, Papaioannou VE, Herold KC: Promotion of beta-cell differentiation in pancreatic precursor cells by adult islet cells. Endocrinology. 2009 Feb; 2008 Oct 9. PMID: 18845629
- Choi JM, Kim SH, Shin JH, Gibson T, Yoon BS, Lee DH, Lee SK, Bothwell AL, Lim JS, Lee SK: Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. Proc Natl Acad Sci U S A. 2008 Dec 16; 2008 Dec 9. PMID: 19066215
- Yi T, Rao DA, Tang PC, Wang Y, Cuchara LA, Bothwell AL, Colangelo CM, Tellides G, Pober JS, Lorber MI: Amelioration of human allograft arterial injury by atorvastatin or simvastatin correlates with reduction of interferon-gamma production by infiltrating T cells. Transplantation. 2008 Sep 15. PMID: 18791454
- Bai Y, Ahmad U, Wang Y, Li JH, Choy JC, Kim RW, Kirkiles-Smith N, Maher SE, Karras JG, Bennett CF, Bothwell AL, Pober JS, Tellides G: Interferon-gamma induces X-linked inhibitor of apoptosis-associated factor-1 and Noxa expression and potentiates human vascular smooth muscle cell apoptosis by STAT3 activation. J Biol Chem. 2008 Mar 14; 2008 Jan 11. PMID: 18192275
- Kawikova I, Leckman JF, Kronig H, Katsovich L, Bessen DE, Ghebremichael M, Bothwell AL: Decreased numbers of regulatory T cells suggest impaired immune tolerance in children with tourette syndrome: a preliminary study. Biol Psychiatry. 2007 Feb 1; 2006 Sep 25. PMID: 16996487
- Nakayama Y, Stabach P, Maher SE, Mahajan MC, Masiar P, Liao C, Zhang X, Ye ZJ, Tuck D, Bothwell AL, Newburger PE, Weissman SM: A limited number of genes are involved in the differentiation of germinal center B cells. J Cell Biochem. 2006 Dec 1. PMID: 16795035
- Chae WJ, Henegariu O, Lee SK, Bothwell AL: The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc Natl Acad Sci U S A. 2006 Jun 20; 2006 Jun 12. PMID: 16769892
- Horowitz MC, Bothwell AL, Hesslein DG, Pflugh DL, Schatz DG: B cells and osteoblast and osteoclast development. Immunol Rev. 2005 Dec. PMID: 16313346
- Zhang Z, Welte T, Troiano N, Maher SE, Fu XY, Bothwell AL: Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice. Biochem Biophys Res Commun. 2005 Mar 18. PMID: 15694417
- Horowitz MC, Xi Y, Pflugh DL, Hesslein DG, Schatz DG, Lorenzo JA, Bothwell AL: Pax5-deficient mice exhibit early onset osteopenia with increased osteoclast progenitors. J Immunol. 2004 Dec 1. PMID: 15557148
- Geirsson A, Bothwell AL, Hammond GL: Inhibition of alloresponse by a human trophoblast non-coding RNA suppressing class II transactivator promoter III and major histocompatibility class II expression in murine B-lymphocytes. J Heart Lung Transplant. 2004 Sep. PMID: 15454174
- Zheng L, Gibson TF, Schechner JS, Pober JS, Bothwell AL: Bcl-2 transduction protects human endothelial cell synthetic microvessel grafts from allogeneic T cells in vivo. J Immunol. 2004 Sep 1. PMID: 15322161
- Torpey N, Maher SE, Bothwell AL, Pober JS: Interferon alpha but not interleukin 12 activates STAT4 signaling in human vascular endothelial cells. J Biol Chem. 2004 Jun 18; 2004 Apr 15. PMID: 15087447
- Schechner JS, Crane SK, Wang F, Szeglin AM, Tellides G, Lorber MI, Bothwell AL, Pober JS: Engraftment of a vascularized human skin equivalent. FASEB J. 2003 Dec. PMID: 14656987
- Zhang Z, Jimi E, Bothwell AL: Receptor activator of NF-kappa B ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis. J Immunol. 2003 Oct 1. PMID: 14500659
- Pober JS, Bothwell AL, Lorber MI, McNiff JM, Schechner JS, Tellides G: Immunopathology of human T cell responses to skin, artery and endothelial cell grafts in the human peripheral blood lymphocyte/severe combined immunodeficient mouse. Springer Semin Immunopathol. 2003 Sep. PMID: 12955465
- Geirsson A, Paliwal I, Lynch RJ, Bothwell AL, Hammond GL: Class II transactivator promoter activity is suppressed through regulation by a trophoblast noncoding RNA. Transplantation. 2003 Jul 27. PMID: 12883198
- Welte T, Zhang SS, Wang T, Zhang Z, Hesslein DG, Yin Z, Kano A, Iwamoto Y, Li E, Craft JE, Bothwell AL, Fikrig E, Koni PA, Flavell RA, Fu XY: STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A. 2003 Feb 18; 2003 Feb 5. PMID: 12571365
- Geirsson A, Lynch RJ, Paliwal I, Bothwell AL, Hammond GL: Human trophoblast noncoding RNA suppresses CIITA promoter III activity in murine B-lymphocytes. Biochem Biophys Res Commun. 2003 Feb 14. PMID: 12565840
- Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R, Schatz DG: Pax5 is required for recombination of transcribed, acetylated, 5' IgH V gene segments. Genes Dev. 2003 Jan 1. PMID: 12514097
- Zheng L, Ben LH, Pober JS, Bothwell AL: Porcine endothelial cells, unlike human endothelial cells, can be killed by human CTL via Fas ligand and cannot be protected by Bcl-2. J Immunol. 2002 Dec 15. PMID: 12471117
- Pflugh DL, Maher SE, Bothwell AL: Ly-6 superfamily members Ly-6A/E, Ly-6C, and Ly-6I recognize two potential ligands expressed by B lymphocytes. J Immunol. 2002 Nov 1. PMID: 12391229
- Li JH, Kluger MS, Madge LA, Zheng L, Bothwell AL, Pober JS: Interferon-gamma augments CD95(APO-1/Fas) and pro-caspase-8 expression and sensitizes human vascular endothelial cells to CD95-mediated apoptosis. Am J Pathol. 2002 Oct. PMID: 12368221
- Kluger MS, Shiao SL, Bothwell AL, Pober JS: Cutting Edge: Internalization of transduced E-selectin by cultured human endothelial cells: comparison of dermal microvascular and umbilical vein cells and identification of a phosphoserine-type di-leucine motif. J Immunol. 2002 Mar 1. PMID: 11859093