James F. Markmann, M.D., Ph.D
Development of Clinical Islet Transplantation at MGH
The research program is focused on approaches to allow beta cell replacement by transplantation in Type I diabetes. This focus has spawned three general areas of study in my laboratory:
- Developing a clinical allogeneic islet transplant program. In 2007 we initiated development of a human pancreatic islet transplant program to serve the New England Region. An islet dedicated GMP compliant production facility was opened in early 2008 on the MGH campus. Since that time, islets have been recovered from more than 40 human pancreata in preparation for human trials. This has allowed facility and process validation and shipping of almost 5 million human islets through a JDRF program to investigators in the BADERC and across the country for use in basic research investigations.
The clinical trial that will begin in the Spring of 2009 will evaluate islet transplantation in Type I diabetics who have already recevied a kidney transplant. We will attempt to improve the initial islet engraftment using a novel agent Xigris in the attempt to abrogate the immediate triggering of coagulation, inflammation and complement that occurs when islets are infused into the liver.
- Defining ways to prevent alloimmune and autoimmue destruction of transplanted beta cells. A major barrier to successful islet transplantation is the immune responses islet incite. Like any foreign tissue, an allogeneic response is triggered to allogeneic islets, but in addition, islets can be destroyed by a recurrence of the autoimmue process that eliminated the native beta cells. A basic research interest has been in utilizing regulatory T cells (Tregs) to promote islet graft survival based on the fact that Tregs have the ability to specifically down-regulate both autoimmue and alloimmune responses. A unique aspects of islets in this regard compared to solid organ transplant is that the Tregs can be co-transplanted with the islet graft, perhaps increasing efficacy and avoiding global immunosuppression.
- Developing strategies to generate beta cells. It is recognized that islet transplantation from cadaveric sources is unable to provide a sufficient supply of beta cells to transplant all the Type I diabetics who could benefit from beta cell replacement and thus will serve as an important platform as novel sources of beta cells are identified. We have sought means to expand endogenous and/or transplanted beta cell mass using transfer of the PDX1 gene. Diabetic mice receiving a direct pancreatic injection of a viral vector encoding PDX1 demonstrate extensive beta cell regeneration apparently from the pancreatic ductal cells. Further studies using lineage tracing are designed to clarify the precursor cell type and in parallel studies we are working to see if PDX1 gene transfer can expand the transplanted beta cell mass.
1. Markmann JF, Lo D, Naji A, Palmiter RD, Brinster RL, Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature 336(6198):476-479, 1988.
2. Posselt AM, Barker CF, Tomaszewski JE, Markmann JF, Choti MA, and Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science 249(4974):1293-1295, 1990.
3. Markmann JF, Posselt AM, Bassiri H, Brayman KL, Woehrle M, Hickey WF, Silvers WK, Barker CF, and Naji A. MHC restricted and non-restricted autoimmune effector mechanisms in BB rats. Transplantation 52(4):662-667, 1991.
4. Deng S, Vatamaniuk M, Lian M, Doliba N, Wang J, Huang X, Liu C, Velidedeoglu E, Desai NM, Raper S, Matschinsky FM, and Markmann JF. Insulin gene transfer enhances the function of human islet grafts transplanted to immunodeficient diabetic mice. Diabetologia, 46:386-393, 2003.
5. Markmann JF, Rosen M, Siegelman E, Soulen M, Deng S, Barker CF, Naji A. MR Defined Periportal Steatosis Following Intraportal Islet Transplantation: A functional Footprint of Islet Graft Survival? (Rapid Publication) Diabetes 52:1591-1594, 2003.
6. Markmann JF, Deng S, Huang X, Desai NM, Velidedeoglu E, Lui C, Frank A, Markmann E, Palajian M, Brayman K, Wolf B, Bell E, Vitamaniuk M, Doliba N, Matschinsky F, Barker CF and Naji A. Insulin independence following isolated islet transplantation and single islet infusions. Annals of Surgery 237(6):741-750, 2003.
7. Deng S, Vatamniuk M, Huang X, Doliba N, Lian MM, Frank A, Velidedeoglu E, Desai NM, Koeberlein B, Wolf B, Barker CF, Naji A, Matschinsky FM, Markmann JF. Structural and functional abnormalities in islets isolated from type II diabetes subjects. Diabetes 53:624-632, 2004.
8. Kobinger GP, Deng S, Louboutin JP, Vatamaniuk M, Rivera VM, Lian MM, Markmann JF, Clackson T, Raper SE, Matschinsky F, Wilson JM.Pharmacologically regulated regeneration of functional human pancreatic islets. Molecular Therapy 11(1):105-11, 2005.
9. Rickels MR, Schutta MH, Mueller R, Markmann JF, Barker CF, Naji A, Teff KL. Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes. Diabetes 54(11):3205-11, 2005.
10. Porrett PM, Yeh H, Frank A, Deng S, Kimg JI, Barker CF, Markmann JF. Availability of suitable islet donors in the United States. Transplantation 2007;84(2):280-2.
11. Lee KM, Yeh H, Zhao G, Wei L, O'Connor M, Stott RT, Soohoo J, Dunussi K, Fiorina P, Deng S, Markmann JF, Kim JI. B cell depletion improves islet allograft survival with anti-CD45RB. Cell Transplant. 2014;23(1):51-8. PMCID: PMC3812388