Research
The Section’s interest is in cellular and molecular mechanisms involved in T cell-mediated, tissue-specific autoimmunity. The questions center on the development and maintenance of self-tolerance to immunologically privileged retinal antigens, and on defining the processes that lead to their pathological breakdown. The goal is to use this knowledge for designing novel and rational strategies for immunotherapy. Approaches and conclusions are generalizable to other tissue-specific autoimmune diseases.
The experimental approaches utilize the model of experimental autoimmune uveoretinitis (EAU) that resembles immune-mediated uveitic diseases in humans. EAU is induced in mice and rats by immunization with retinal antigens or their fragments. The hereditary mechanisms that predispose to uveitis are studied by using EAU-susceptible and EAU-resistant strains of rodents and DNA microarrays. Uveitogenic T cell lines and clones are developed and studied, with the aim of devising ways to target the autopathogenic cells in vivo. Genetically altered (transgenic and “knockout”) mice are used to evaluate the role of various components of the immune system in the immunopathogenesis of uveitis. Various strategies to induce long-lasting immunological tolerance to retinal antigens are explored as immunotherapy for EAU. Selected questions for which appropriate tools are not yet available in the EAU model are studied using related autoimmune disease models, e.g., experimental autoimmune encephalomyelitis (EAE). Lastly, EAU serves as a template for the preclinical evaluation of new drugs and compounds as to their effects on the various stages of immunopathogenesis and disease expression.
Subjects under study include:
Staff of the NEI’s Immunoregulation Section. Front row (left to right): Reiko Horai, Phyllis Silver, Carlos Zarate-Blades, Bill McManigle, Ru Zhou. Back row (left to right): WeiPo Chong, Mary Mattapallil, Rachel Caspi, Anna Hansen.
- Genetic and genomic basis of susceptibility to uveitis
- Characterization of genes associated with susceptibility and resistance by genetic and genomic methods using chromosome-substituted rat strains
- identification of pathogenic epitopes and T cell repertoire selection that might be associated with human disease using HLA-transgenic mice
- Development and maintenance of tolerance to retinal antigens using transgenic and knockout mice with altered expression of retinal antigens and retinal antigen-specific T cell receptors
- Role of central and peripheral mechanisms in tolerance to retinal antigens
- Ocular immune privilege and its role in autoimmunity to retinal antigens
- Regulatory T cells in control of uveitis
- Regulation of retina-specific T cells by ocular resident cells
- Immunopathogenesis of uveitis
- Effector T cell responses (Th1, Th2 & Th17) in pathogenesis of uveitis
- The role of the innate immunity: M, NKT and other innate cells in EAU
- Cytokines and cytokine receptors as targets for immunotherapy
Specific information on the recent and current work of the Sectioncan be found in the NIH Annual Reports database:
Staff
| Name | Title | |
|---|---|---|
Rachel Caspi, Ph.D. |
Section Head | rcaspi@helix.nih.gov |
| Phyllis Silver, B.S. | Biologist | silverp@nei.nih.gov |
| Anna Hansen, Ph.D. | Postdoctoral Fellow | hansena@nei.NIH.gov |
| Reiko Horai, Ph.D. | Staff Scientist | hreiko@mail.NIH.gov |
| Mary Mattapallil, DVM, Ph.D. | Staff Scientist | mattapallilm@nei.nih.gov |
| Ru Zhou, Ph.D. | Postdoctoral Fellow | zhour2@nei.nih.gov |
| WiaPo Chong, Ph.D. | Postdoctoral Fellow | waipoc@mail.nih.gov |
| Carlos Blades, Ph.D. | Postdoctoral Fellow | bladescr@mail.nih.gov |
| Jennifer Kielczewski, Ph.D. | Postdoctoral Fellow | jennifer.kielczewski@nih.gov |
| Jun Chen | Research Associate (contractor) | chenju@mail.nih.gov |
Recent Publications
Selected Review Papers
Pennesi, G and R.R. Caspi. Genetic control of susceptibility in clinical and experimental uveitis. International Reviews of Immunology 21:67-88, 2002. (Download as PDF file) *
R.K. Agarwal and R.R. Caspi Rodent models of experimental autoimmune uveitis (EAU). In: Autoimmunity: Methods and Protocols, pp. 395–419, A. Perl (ed), Humana Press, NY (2004).
(Download as PDF file) *
Caspi, R.R. Animal models of autoimmune and immune-mediated uveitis. In: Drug Discovery Today: Disease Models. (Daniel Altman, issue Ed.) 3:3-9, 2006
(Download as PDF file) *
Caspi, R.R. Mechanisms Underlying Autoimmune Uveitis In: Drug Discovery Today: Disease Mechanisms. (T. Delovitch and D. Scott, Ed.), 3:199-206, 2006.
(Download as PDF file) *
Caspi, R.R. Ocular autoimmunity: The price of privilege? Immunol Rev. 213:23-35, Andrew Mellor and David Munn (issue eds). 2006.
(Download as PDF file) *
Caspi, R.R. A look at autoimmunity and inflammation in the eye. J Clin Invest. 120:3073-83. 2010.
(Download as PDF file) *
Selected Research Papers
Caspi, R.R., F.G. Roberge and R.B.Nussenblatt: Organ-resident nonlymphoid cells suppress autoimmuneT-helper lymphocytes. Science 237:1029-1032, 1987. (Medline)
Caspi, R.R., F.G. Roberge, C.-C. Chan, B.Wiggert, C.J. Chader, L.A. Rozenszajn, Z. Lando and R. B.Nussenblatt. A new model of autoimmune disease:experimental autoimmune uveoretinitis induced in mice with twodifferent retinal antigens. J. Immunol. 140:1490-1495,1988. (Medline)
Roberge, F.G., R.R. Caspi and R.B.Nussenblatt. Glial retinal Muller cells produce IL1 activity andhave a dual role in regulation of autoimmune T-lymphocytes: antigenpresentation manifested after removal of suppressive activity. J.Immunol. 140:2193-2196, 1988. (Medline)
Helbig, H., R.C. Gurley, A.G. Palestine,R.B. Nussenblatt and R.R. Caspi. Dual role of ciliary body cellsin regulation of T-lymphocyte proliferation. Eur. J. Immunol.20:2457-2463, 1990. (Medline)
Hara, Y., R.R. Caspi, B. Wiggert, C.C.Chan, G.A. Wilbanks and J.W. Streilein. Suppression of experimentalautoimmune uveitis in mice by induction of anterior chamber associatedimmune deviation with interphotoreceptor retinoid binding protein. J.Immunol. 148:1685-1692, 1992.(Medline)
Caspi, R.R., C.-C. Chan, B.G. Grubbs G.J.Chader and B. Wiggert. Genetic control of susceptibility toexperimental autoimmune uveoretinitis in the mouse model: Concomitant regulation by MHC and non-MHC genes. J. Immunol.148:2384-2389, 1992. (Medline)
Caspi, R.R., C. Parsa, C.C. Chan, B.G.Grubbs, S. Bahmanyar, H. Heremans, A. Billiau and B. Wiggert. Endogenous systemic Interferon-gamma has a protective role againstocular autoimmunity in mice. J. Immunol. 152:890-899, 1994. (Medline)
Rizzo, L.V., N.E. Miller-Rivero, C.C. Chan, B. Wiggert, R.B. Nussenblatt and R.R. Caspi.Interleukin-2 treatment potentiates induction of oral tolerance. J.Clin. Invest. 94:1668-1672, 1994. (Medline)
Silver, P.B., L.V. Rizzo, C.C. Chan, L.A.Donoso, B. Wiggert, and R.R. Caspi. Identification of a majorpathogenic epitope in the IRBP molecule recognized by mice of theH-2r haplotype. Invest. Ophthalmol. Vis. Sci/ 36:946-954,1995. (Medline)
Caspi, R.R., P.B. Silver, C-C.Chan, B. Sun, R.K. Agarwal, J. Wells, S. Oddo, Y. Fujino, F. Najafianand R.L. Wilder. Genetic susceptibility to experimental autoimmuneuveoretinitis (EAU) in the rat is associated with an elevated Th1response. J. Immunol. 157:2668-2675, 1996. (Medline)
Nussenblatt, R.B., I. Gery, R. Ferris, J.Shiloach, N. Ramaley, C. Perry, R.R. Caspi, C.S. Foster, H. L.Weiner and S. M. Whitcup. Treatment of Uveitis by Oral Administrationof Retinal Antigens: Results of a Phase I/II Randomized MaskedTrial Am. J. Ophthalmol. 123:583-592, 1997. (Medline)
Jones, L.S., L.V. Rizzo, R. K. Agarwal,T.K. Tarrant, C.C. Chan, B.Wiggerrt and R.R. Caspi. Interferon gamma-deficient mice developexperimental autoimmune uveitis in the context of a deviant effectorresponse. J. Immunol. 158:5997-6005, 1997. (Medline)
Sun, B., L.V. Rizzo, S.H Sun C.C. Chan,B. Wiggert, R.L. Wilder andR.R. Caspi. Genetic susceptibility to EAU involves more than apredisposition to generate a Th1 or a Th2-type response J. Immunol.159:1004-1011, 1997. (Medline)
Prendergast, R.A., C.E. Iliff, N.M.Coskuncan, R.R. Caspi, G.Sartani, T.K. Tarrant, G.A. Lutty, D.S. McLeod. T cell traffic and theinflammatory response in experimental autoimmune uveoretinitis. Invest.Opthalmol. Vis. Sci. 39:754-762, 1998. (Medline)
Rizzo, L.V., L.R. Stiff, B. Wiggert andR.R. Caspi. The role ofIL-10 in natural and therapeutic regulation of EAU. InternationalImmunology 10:807-814, 1998.(Medline)
Tarrant, T.K., P.B. Silver, C.C. Chan andR.R. Caspi. EndogenousIL-12 is required for induction and expression of experimentalautoimmune uveitis. J. Immunol. 161:122-127, 1998. (Medline)
Tarrant, T. K., P. B. Silver, J. L.Wahlsten, L. V. Rizzo, C. C.Chan, B. Wiggert, and R. R. Caspi. Interleukin 12 protects from a Thelper type 1-mediated autoimmune disease, experimental autoimmuneuveitis, through a mechanism involving interferon gamma, nitric oxide,and apoptosis. J Exp Med 189:219-230 (1999). (Medline)
Agarwal, R. K., C. C. Chan, B. Wiggert,and R. R. Caspi. Pregnancyameliorates induction and expression of experimental autoimmuneuveitis. J Immunol 162:2648-2654 (1999). (Medline)
Rizzo, L. V., R. A. Morawetz, N. E.Miller-Rivero, R. Choi, B.Wiggert, C. C. Chan, H. C. Morse, 3rd, R. B. Nussenblatt, and R. R.Caspi. IL-4 and IL-10 are both required for the induction of oraltolerance. J Immunol 162:2613-2622 (1999). (Medline)
Shu-Hui Sun, Phyllis B. Silver, Ying Du,Rachel R. Caspi, Ronald L.Wilder, and Elaine F. Remmers. Genetic analysis of experimentalautoimmune uveoretinitis (EAU) in rats. Int. Immunol. 11:529-534(1999). (Medline)
Silver, P.B. , C.C. Chan, B.Wiggert andR.R. Caspi. The requirementfor pertussis toxin for induction of EAU is strain-dependent: B10.RIIImice develop EAU without pertussis treatment. Invest. Opthalmol. Vis.Sci. 40:2898-2905 (1999). (Medline)
Avichezer, D., P.B. Silver, C.C Chan, B.Wiggert and R.R. Caspi.Identification of a new epitope of human IRBP that induces autoimmuneuveoretinitis in H-2b haplotype mice. Invest. Opthalmol.Vis. Sci. 41:127-131 (2000). (Medline)
Xu, H., E.F. Wawrousek, T.M. Redmond,J.M. Nickerson, B. Wiggert,C.C. Chan, and R.R. Caspi. Transgenic expression of an immunologicallyprivileged retinal antigen extraocularly reduces susceptibility toexperimental autoimmune uveitis. Eur. J. Immunol. 30:272-278 (2000) (Medline)
Agarwal, R.K., R.K., Y. Kang, E.Zambidis, D.W. Scott, C.C. Chan andR.R. Caspi. Retroviral Gene transfer of an immunoglobulin-antigenfusion construct protects from Experimental autoimmune uveitis. J.Clin. Invest. 106:245-252, 2000. (Medline)
Wahlsten, J.L., H.L. Gitchell, C.C. Chan,B. Wiggert and R. Caspi.Fas and FasL expressed on cells of the immune system, not on the targettissue, control induction of experimental autoimmune uveoretinitis.J. Immunol. 165:5480-5486, 2000. (Medline)
Silver, P.B., K.S. Hathcock, C.C. Chan,B. Wiggert, and R.R. Caspi.Costimulatory blockade inhibits a primary episode ofexperimentalautoimmune uveoretinitis, but does not lead to long termtolerance. J. Immunol. 165:5401-5407, 2000. (Medline)
Su SB, Silver PB, Zhang MF, Chan CC,Caspi RR. Pertussis Toxininhibits induction of tissue specific autoimmune disease by disruptingG-protein coupled signals. J. Immunol. 167:250-256, 2001. (Medline)
Wang, Peng , SH Sun, PB Silver, CC Chan,B Wiggert . Methimazoleprotects from experimental autoimmune uveitis (EAU) by inhibitingantigen presenting cell function and reducing antigen priming. J.Leukocyte Biol. 73:57-64, 2003. (Medline)
Pennesi, G., M.J. Mattapallil, S.H. Sun,D. Avichezer, P.B. Silver,Z. Karabekian, C.S. David, P.A. Hargrave, J.H. McDowell, W.C. Smith, B.Wiggert, L.A. Donoso, C.C. Chan and R.R. Caspi. A humanized model ofexperimental autoimmune uveitis in HLA class II-transgenic mice. J.Clin Invest. 111:1171-1180, 2003. (Medline)
Su, S-B., P.B. Silver, P. Wang, C.C. Chan and R.R. Caspi. Dissociatingthe Enhancing and Inhibitory Effects of Pertussis Toxin on AutoimmuneDisease. J. Immunol 171:2314, 2003. (Medline)
Hui Xu, Phyllis B. Silver, Teresa K. Tarrant, Chi-Chao Chan and RachelR. Caspi. TGF-b Inhibits Activation and Uveitogenicity of Primary butnot of Fully Polarized Retinal Antigen-Specific Memory/Effector Tcells. Invest. Opthalmol. Vis. Sci. 44:4805-4812, 2003. (Medline)
Avichezer, D., R.S. Grajewski, C.-C. Chan, M.J. Mattapallil, P.B.Silver, J.A. Raber, G.I. Liou, B. Wiggert, G.M. Lewis, L.A. Donoso, andR.R. Caspi. An Immunologically Privileged Retinal Antigen ElicitsTolerance: Major Role for Central Selection Mechanisms J. Exp. Med.,198:1665-1676, 2003. (Medline)
Su, S-B., P.B. Silver, P. Wang, C.C. Chan and R.R. Caspi. Cholera toxinprevents Th1-mediated autoimmune disease by enhancing Th2 polarization.J. Immunol., 173: 755–761, 2004 (Medline)
Bagenstose, LM, RK Agarwal, PB Silver, MHarlan, SC. Hoffmann, RL.Kampen, CC Chan and RR. Caspi. Disruption of CD40/CD40L interactions ina retinal autoimmunity model results in protection without tolerance.J. Immunol, 175: 124–130, 2005. (Medline)
Karabekian, Z., Simon D. Lytton, PhyllisB. Silver, Y. Sergeev, J.P.Schneck and R.R. Caspi. Antigen/MHC class II/Ig dimers for study ofuveitogenic T cells: IRBP p161-180 presented by both IA and IEmolecules. Invest. Opthalmol. Vis. Sci.46:3769-3776, 2005. (Medline)
Su, S-B, PB. Silver, R.S. Grajewski,R.K. Agarwal, J. Tang, C.C.Chan and R.R. Caspi. Essential Role of the MyeloidDifferentiation Factor 88 (MyD88) Pathway, but Nonessential Rolesof Toll Receptors 2, 4 and 9, in the Adjuvant Effect Promoting Th1Mediated-Autoimmunity. J. Immunol. 175:6303-6310. (Medline)
Grajewski, RS, PB Silver, RK Agarwal, SB Su, CC Chan, GI. Liou and RR. Caspi. Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ T-regs that protect from IRBP-induced retinal autoimmunity. J. Exp. Med.203:851-856, 2006. (Medline)
Jason DeVoss, Yaefi Hou, Lawrence Fong, Rachel Caspi, Gregory I Liou, John Rinn, Howard Chang, Mark S Anderson. Spontaneous autoimmunity prevented by thumic expression of a single self antigen. J. Exp. Med. 2-3, 2727-2735, 2006. (Medline)
Jun Tang, Wei Zhu, Phyllis B Silver, Shao-Bo Su, Chi-Chao Chan, and Rachel R Caspi. A new model of retinal autoimmunity: autoimmune uveitis elicited with antigen-pulsed dendritic cells is driven by unique effector mechanisms. J. Immunol. 2007 J. Immunol. 178:5578-5587, 2007 (Medline)
Phyllis B. Silver, Rajeev K. Agarwal, Shao-Bo Su, Rafael S. Grajewski, Chi-Chao Chan, John M. Nickerson and Rachel R. Caspi. Hydrodynamic Vaccination with DNA encoding an immunologically privileged retinal antigen protects from anti-retinal autoimmunity through induction of regulatory T cells. J. Immunol.,179:5146-58, 2007 (Medline)
Mattapallil, MJ, A Augello, C Cheadle, D Teichberg, KG Becker, JJ Mattapallil, CC Chan, G Pennesi and RR Caspi Differentially expressed genes in MHC-compatible rat strains that are susceptible or resistant to ocular autoimmunity. Invest. Ophthalmol. Vis. Sci. 49:1957-70, 2008. (Medline)
Cortes LM, Mattapallil MJ, Silver PB, Donoso LA, Liou GI, Zhu W, Chan CC, Caspi RR. Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice Invest. Opthalmol. Vis. Sci., 49:1946-56, 2008. (Medline)
Dror Luger, Phyllis B. Silver, Jun Tang, Daniel Cua, Zoe Chen, Yoichiro Iwakura , Edward P. Bowman, Nicole M. Sgambellone, Chi-Chao Chan and Rachel R. Caspi. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205:799-810, 2008. (Medline)
Agarwal RK, Horai R, Viley AM, Silver PB, Grajewski RS, Su SB, Yazdani A, Wei Zhu, Kronenberg M, Murray PJ, Rutschman RL, Chan CC and Caspi RR. Abrogation of anti-retinal autoimmunity in IL-10 transgenic mice due to reduced T cell priming and inhibition of effector mechanisms. J. Immunol. 80:5423-9, 2008. (Medline)
Rachitskaya AV*, Hansen AM*, Horai R, Li Z, Luger D, Villasmil R, Nussenblatt RB and Caspi RR. NKT cells constitutively express IL-23 receptor and RORgt, and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J. Immunol Cutting Edge, 180:5167-71, 2008. (Medline)
Mattapallil MJ, Sahin A, Silver PB, Sun SH, Chan CC, Hansen CT, Remmers EF, Hejtmancik JF and Caspi RR. Common genetic determinants of uveitis shared with other autoimmune disorder J. Immunol. 180:6751-9, 2008. (Medline)
Cortes LM, Avichezer D, Silver PB, Luger D, Mattapallil MJ, Chan CC and Caspi RR. Inhibitory Peptide Analogs Derived from a Major Uveitogenic Epitope Protect from Anti-Retinal Autoimmunity by Inducing Type 2 and Regulatory T Cells. J. Leukoc. Biol. 2008 May 21. [Epub ahead of print]. (Medline)
Grajewski RS*, Hansen AM*, Agarwal RK, Kronenberg M, Sidobre S, Su SB, Silver PB, Tsuji M, Franck RW, Lawton AP, Chan CC and Caspi RR. Activation of iNKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-_ production and dampening of the adaptive Th1 and Th17 responses J. Immunol, 181:4791-4797 (2008). *Equal first authors. (Medline)
Caspi, R.R. Immunotherapy of autoimmunity and cancer: the penalty for success. Nat. Rev, Immunol. 8:970-9766, 2008. (Medline)
Jun Tang, Dror Luger, Wei Zhu, Phyllis B Silver, Rafael Grajewski, Shao-Bo Su, Chi-Chao Chan, Luciano Adorini and Rachel R Caspi. Calcitriol suppresses anti-retinal autoimmunity through inhibitory effects on the Th17 effector response J. Immunol, 182:4624-4632, 2009. (Medline)