Mechanisms regulating the maintenance and loss of immune tolerance to tissue specific antigens in autoimmune diseases and transplantation
Autoimmune diabetes serves as an important paradigm for the loss of immune tolerance to tissue specific autoantigen(s) mediated by the activation of islet-reactive T lymphocytes. The non-obese diabetic (NOD) mouse is an excellent model for study of the immune pathogenesis of human insulin-dependent diabetes mellitus. NOD mice spontaneously develop overt diabetes as a result of the selective, T cell mediated destruction of insulin producing b cells of the islets of Langerhans. Elucidation of the cellular nature of the antigen presentation driving the evolution of a destructive anti-islet T cell response is one main focus of the laboratory. Based on our finding that B cell deficient NOD mice are fully resistant to the development of autoimmune diabetes, we have hypothesized that the progression of the islet-specific T cell response in NOD mice is dependent on antigen presentation by B lymphocytes. Specifically, ongoing research is focused on determining the role of: 1) MHC class II mediated cognate T/B collaboration and 2) BCR and non-BCR mediated means of antigen uptake by APCs in NOD diabetogenesis.
Another major effort in the laboratory is the elucidation of the mechanisms contributing to the maintenance of T cell tolerance and the parameters favoring its dysregulation. The fate and activation requirements of T cells specific for tissue restricted neo- and allo- antigens will be studied in the context of spontaneous autoimmune disease and following transplantation of cellular and solid organ allografts. Specifically, an MHC class II restricted, CD4+ TCR transgenic model is utilized to study the phenotype, homing patterns, and pathogenic potential of autoreactive T cells, 1) developing in the milieu of tissue restricted neo-antigen expression and 2) encountering neo- antigens present in transplanted organs. Furthermore, using bone marrow chimeras we have investigated the mechanisms of immunologic tolerance mediated by T cell deletion and anergy to alloantigens. Ongoing studies are focused on defining the antigen presenting requirements determining the shape of the alloreactive T cell repertoire and its functional state. Understanding the basic parameters dictating the state of tolerance and activation requirements of T cells reactive to tissue restricted autoantigens, as well as alloantigens, will permit the design of therapeutic means aimed at modulating the response of auto- and allo-reactive T cells.
Jordan, M.S., Boesteanu, A., Reed, A.J., Petrone, A.L., Holenbeck, A., Lerman, M.A., Naji, A., and Caton, A.J.: Thymic Selection of CD4+ CD25+ Regulatory T Cells Induced by an Agonist Self-Peptide. Nature Immunology. 2(4): 301-306, April 2001.
Alfrey EJ, Campos L, Naji A, Barker CF, and Dafoe DC: Liver Allografts Confer Donor Specific Tolerance to Transplanted Islets in Rats. 2001 Notes: In Press.
Greeley SAW, Moore DJ, Noorchashm H, Noto L, Rostami SY, Schlachterman, A, Song HK, Koeberlein B, Barker CF, and Naji A: Impaired Lymph Node CD4 T-Cell Activation in MT-/-NOD Mice. 2001 Notes: Submitted.
Wu, H., Wasik, MA., Haynes, B., Moore, H.C.F., Leonard, D.G.B., Montone, K.T., Kamoun, M., Przybylski, G., Naji, A., Tomaszewski, J., and Salhany, K.: Hepatosplenic γδ T-Cell Lymphoma as a Late-Onset Posttransplant Lymphoproliferative Disorder in Renal Transplant Patients. American Journal of Clinical Pathology. 113(4): 487-496, April 2000.
Shaw, L.M., Korecka, M., Aradhye, S., Grossman, R., Bayer, L., Innes, C., Cucciara, A., Barker, C., Naji, A., Nicholls, A. and Brayman, K.: Mycophenolic Acid Area Under the Curve Values in African American and Caucasian Renal Transplant Patients are Comparable. Journal of Clinical Pharmacology. 40(6): 624-633, June 2000.
Noorchashm, H., Moore, D.J., Noto, L.E., Noorchashm, N, Reed, A.J., Reed, A.L., Song, H.K., Mozaffari, R., Jevnikar, A.M., Barker, C.F., and Naji, A.: Impaired CD4 T Cell Activation Due to Reliance upon B-Cell Mediated Costimulation in Non-Obese Diabetic (NOD) Mice. Journal of Immunology. 165: 4685-4696, October 2000.
Larson, R.A., Naji, M., Lombardi, J.V., Naji, A., Koeberlein, B., Golden, M.A. Ryan, S.: Adenoviral-Mediated Uteroglobin Gene Transfer Inhibits Neointimal Hyperplasia after Balloon Injury in the Rat Carotid Artery. Journal of Vascular Surgery. 32(6): 1111-1117, December 2000.
Noorchashm, H., Moore, D.J., Lieu, Y.K., Noorchashm, N., Schlacterman, A., Song, H.K., Lambris, J.D., Barker, C.F., and Naji, A.: Contribution of the Innate Immune System to Autoimmune Diabetes: A Role for the Cr1/Cr2 Complement Receptors. Cellular Immunology. 195(1): 75-79, July 1999.
Noorchashm H., Lieu Y.K., Noorchashm N, Rostami S.Y., Greeley, S.A.S., Schlacterman A., Song H.K., Noto, L.E., Jevnikar A.M., Barker C.F., and Naji A.: I-A g7-Mediated Antigen Presentation by B Lymphocytes Is Critical in Overcoming a Checkpoint in T Cell Tolerance to Islet β Cells of Nonobese Diabetic Mice. Journal of Immunology. 163(2): 743-750, July 1999.
Song, H.K., Noorchashm, H., Lieu, Y.K., Rostami, S., Greeley, S.A.S., Barker, C.F., and Naji, A.: Tracking Alloreactive Cell Division In Vivo. Transplantation. 68(2): 297-299, July 1999.
back to top
Last updated: 08/14/2012
The Trustees of the University of Pennsylvania