Alexei Savinov, MD, PhD, Lab


Pathogenesis of autoimmune diseases is extremely complex. My main interest is an organ-specific diseases such as autoimmune Type I Diabetes (T1D), and we have variety of mouse models developed for this disease. Progression of T1D involves the activation of autoimmune T cells, consequent homing of activated lymphocytes to the pancreatic islets, and ensuing destruction of insulin-producing beta cells. Our studies focus on determining how autoimmune T cells are initially activated during T1D pathogenesis, how they home to the target organ, and how they destroy their beta cell targets, causing clinical onset of T1D. The main goal of research projects in my laboratory is to design and exploit tools for the manipulation of adaptive autoimmunity for therapeutic purposes. To achieve this goal we use the variety of genetic, molecular biological, and biochemical approaches.

The major project in my lab focuses on the interaction between activated lymphocytes and endothelial cells in the pancreatic islets during the development of T1D, which is the hallmark of the diabetogenic T cells homing process. Initial adhesion, firm adhesion and diapedesis of lymphocytes are the three crucial steps involved in the homing process. To address the issue of the homing of diabetogenic T cells to their target tissue, we used insulin-specific CD8+ T cells (IS-CD8+). Our studies of the molecular mechanisms of IS-CD8+ cell trafficking to the islets revealed a specific mechanism controlling initial stages of homing of autoimmune cells, which includes combination of endothelial cross-presentation of islet antigen with the signaling of CCL21 chemokine. Investigating the later stage of diabetogenic T cells homing, diapedesis, we found its strong dependence on a series of proteolytic events mediated by matrix metalloproteinases. Using the small molecule matrix metalloproteinase inhibitor we were able to specifically repress the diabetogenic T cell transmigration and homing processes as opposed to causing general immunosuppression. Moreover, specific inhibition of T cell intra-islet transmigration by small molecule matrix metalloproteinase inhibitor restored beta cell functionality, increased insulin-producing beta cell mass, and alleviated the severity of T1D in acutely diabetic NOD mice. As a result, acutely diabetic NOD mice did not require insulin injections for survival for a significant time period, thus providing a promising clue to effect T1D reversal in humans.

Therapeutic interventions leading to beta cell regeneration and the reversal of established T1D are exceedingly limited. Thus, additional research projects in my lab focuses on the identification of the endogenous stimuli with potential ability to induce beta-cell development and regeneration in vivo in mouse models. We believe that combining therapies capable of limiting/ reversing autoimmune attack with ones aimed to induce endogenous beta cell proliferation/neogenesis is the logical and effective step on the road to developing a definitive therapy forT1D.


Contact Information for Savinov Lab:

Alexei Savinov, MD, PhD
Associate Scientist of The Sanford Project
Sanford Health 
Sanford Research Center
2301 East 60th Street North
Sioux Falls, SD 57104
Phone: 605-312-6019


Lab News

April 2017 Alexei Savinov, PhD, was awarded a research grant from BioSNTR for his project, "Assessing Whole-cell PRPN22 interactome in macrophages."

May 2016, Dr. Alexei Savinov delivered an oral presentation entitled "Assessing whole-cell PTPN22 interactome in T cells with BioID" on April 28th at the Cold Spring Harbor Symposium on Gene Expression and Signaling in the Immune System in Cold Spring Harbor, NY.

January 2016, The laboratory of Dr. Alexei Savinov, including postdoctoral fellows Drs. Ilian Radichev and Lillianna Maneva-Radicheva and Sanford/USD graduate students Christina Amatya and Maryam Salehi, recently published a study from their laboratory entitled “Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes” in the Journal of Immunology.

December 2015, The Savinov team, including Drs. Alexei Savinov and Ilian Radichev and graduate student Maryam Salehi were co-authors on a recent publication in the Journal of the American Heart Association entitled “Transgenic Overexpression of Tissue-Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification.”