Xunrong Luo, MD, PhD Assistant Professor Medicine and Surgery Tolerance mechanisms in autoimmune diabetes Curricula: Immunology and Microbial Pathogenesis E-mail:   xunrongluo@northwestern.edu

The main focus of research in my laboratory is tolerance mechanisms in autoimmune diabetes and in allogeneic islet cell transplantation, a form of cure for autoimmune diabetes.  There are 3 main areas of ongoing research:

1.     Ex vivo induction and expansion of antigen-specific regulatory T cells as a form of cell immunotherapy for tolerance induction.  Using TCR transgenic T cells recognizing a diabetogenic epitope of which a mimetope peptide is known as the BDC peptide, we made the original observation that naïve CD4+CD25-Foxp3- T cells can be induced by peptide pulsed splenic dendritic cells to become CD4+CD25+Foxp3+ T cells in the presence of transforming growth factor b1 in tissue culture (PNAS 104(8): 2821-6, 2007).  These ex vivo induced Tregs suppress autoimmune diabetes in both spontaneously diabetic NOD mice as well as in NOD.scid mice adoptively transferred with diabetogenic cells.  Ongoing effort is focusing on inducing and expanding such antigen-specific Treg cells from a wild-type polyclonal, rather than TCR transgenic, repertoire for potential use as a form of cell immunotherapy in clinically relevant settings.  The antigens of interest are both diabetogenic antigens implicated in the pathogenesis of autoimmune diabetes as well as allo-antigens implicated in transplant rejections.  In addition to therapeutic outcomes, ongoing experiments also address the stability, trafficking, cell-cell interactions and infectious tolerance upon adoptive transfer of these ex vivo induced antigen-specific Tregs. 

2.     The role of extracellular regulated kinase (ERK) in CD4+CD25+Foxp3+ Treg cell differentiation and transplant tolerance.  In a recent study, we made the original observation that in the process of conversion of CD4+CD25-Foxp3- T cells to CD4+CD25+Foxp3+ T cells by TGF-b1 in vitro, phosphorylation of ERK was significantly inhibited, which in term led to down-regulation of DNA methyl-transferases and promoter demethylation of the FOXP3 gene (JI 180(5): 2757-61, 2008).  We now have obtained transgenic mice with controllable (by a tetracycline controlled transactivator system) and T cell-specific inhibition of ERK phosphorylation.  Ongoing effort is focusing on the role of ERK inhibition in CD4+CD25+Foxp3+ Treg differentiation in vivo and its contribution to transplant rejection and/or transplant tolerance induction in setting of T cell activation by allo-antigens.  Future experiments will also address the contribution of patterns of epigenetic regulation by gene promoter methylation and demethylation in transplant rejection and/or transplant tolerance.

3.     Transplant tolerance induction using donor cell infusion treated with ethylcarbodiimide (ECDI).  Using a stringent full MHC-mismatched strain combination, we have shown in an allogeneic islet cell transplant model that two infusions of ECDI-treated donor cells prior to and after transplantation led to indefinite graft survival in over 70% of the transplant recipients in the absence of any immunosuppression.  This tolerance to the allogeneic islet graft is associated with up-regulation of CD4+CD25+Foxp3+ Treg cells, and significant down-regulation of anti-donor T and B cell responses.  Current effort is focusing on dissecting the role of various host elements (including various cell types - dendritic cells, macrophages, B cells, and T cells – as well as signaling pathways) that are crucial in the effective induction of donor specific tolerance; and delineating the critical differences between non-autoimmune strain (such as C57BL/6) and autoimmune strain (such as NOD) to understand the cellular and/or molecular defect(s) that are the obstacles for tolerance induction in the NOD mice.

Publications:

Luo, X., Yang H, Kim I-S, Sainte-Hilaire F, Thomas D, De B, Hancock WW, Crystal RG, Suthanthiran  (2005) Systemic TGF-b1 gene therapy restores self-tolerance and facilitates islet regeneration in overt diabetic NOD mice.  Transplantation  79(9): 1091-1096.

Tambur, A.R., Buckingham, M., McDonald, L., Luo, X.  Development of Donor-Specific and Non-Donor-Specific HLA-DP Antibodies Post-Transplant: the Role of Epitope Sharing and Epitope Matching. (2006)  Clinical Transplants: 399-404.

Tarbell V.K., Petit L., Zuo X., Toy P., Luo X., Mqadmi A., Yang H., Suthanthiran M., Mojsov S., Steinman RM. (2007) Dendritic cell expanded, islet-specific, CD4+CD25+CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice.  J Exp Med 204(1): 191-201.

Luo, X., Tarbell KV, Yang H, Pothoven K, Bailey SL, Ding R, Steinman RM, Suthanthiran M. (2007)  Dendritic cells with TGF-b1 differentiate naïve CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Nat Acad Sci 104 (8): 2821-2826

Yang H, Ding R, Sharma VK, Hilaire FS, Lagman M, Li B, Thomas DA, Luo X, Song P, Stauffer C, August P, Suthanthiran M.  (2007)  Hyperexpression of Foxp3 and IDO during acute rejection of islet allografts.  Transplantation 83(12): 1643-7.

Luo, X., Zhang, Q., Liu, V., Xia, Z., Pothoven, K.L., Lee, C. (2008)  Cutting Edge: TGF-b-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK.  J of Immunology 180: 2757-2761.

Luo, X., Rajagopal A, Ison M, Friedewald J, Leventhal J, Kanwar Y. (2008) Two rare forms of renal allograft glomerulopathy during cytomegalovirus infection and treatment.  American Journal of Kidney Diseases  51(6): 1047-51

View Publications by Xunrong Luo listed in the National Library of Medicine (PubMed).

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