Although many diabetic patients in renal failure, especially children, have potential donors willing to provide both a kidney and islets, the quantity of islets necessary to achieve insulin independence hampers successful islet Tx by partial pancreatectomy from living donors. Project 2 is designed toward developing a tolerance-inducing strategy for curative treatment of end-stage diabetic nephropathy using living donor composite Islet-Kidney (IK) transplantation (Tx). We have previously demonstrated that the strategy of transplanting pre-vascularized islets as part of IKs in large animal models is successful, using far fewer islets than are required for Tx of free, non-vascularized islets. Both renal and islet function were restored by IK Tx across fully allogeneic barriers in nephrectomized diabetic baboons using a clinically relevant immunosuppression protocol. More recently, our preliminary data have shown the successful induction of tolerance of IKs in rhesus monkeys treated with hematopoietic cell Tx in a """"""""mother-to-son"""""""" combination. In order to transition the IK strategy to clinical applicability, and thus justify the additional donor risk required for IK preparation, the present studies are directed toward achieving consistent tolerance induction to IKs with our historical bone marrow (BM) chimerism regimen, as well as determining the minimal degree of pancreatectomy required for successful IK creation. These studies will be carried out using cynomologous monkeys and our BM Tx conditioning regimen that has already been introduced into human protocols and continues to be refined for more widespread clinical application (see Project 1 of this U19). We will first determine whether tolerance and long-term islet function can be induced reproducibly across both one-haplotype and fully mismatched barriers, in order to determine whether this strategy will be applicable for both living related and unrelated donor combinations (Aim 1). We will then assess the optimal timing of IK Tx in relation to BM Tx for tolerance induction, as well as assess the minimal donor pancreatectomy required for IK preparation (Aim 2). Finally, we will examine the effects of recipient age, memory T-cells (Tmem), and innate immune reactivity on the induction of tolerance, utilizing appropriate strategies, including thymic rejuvenation, T-mem depletion (in conjunction with Project 1) and inhibition of inflammation (Core B), respectively, to overcome these anticipated barriers (Aim 3). We will study the effects of adaptive and innate immune factors on tolerance induction in collaboration with Project 3 for all three aims. Among the advantages of this approach in the treatment of end-stage diabetic nephropathy, in contrast to current clinical management, are that it would obviate the need for chronic immunosuppresion, avoid the morbidity associated with whole organ pancreas Tx, and circumvent the long wait list times currently required for deceased donor Tx by providing euglycemia with limited islet volume safely obtained from living donors.

Public Health Relevance

Although many diabetic patients in renal failure, especially children, have potential donors who would be willing to donate both a kidney and a portion of their pancreas, the quantity of islets necessary to achieve insulin independence is currently far greater than is obtainable from the amount of pancreas that can safely be removed from the living donor. This research proposal is directed towards an approach that combines islets and a kidney into a composite islet-kidney, not only requiring a much lower number of donor islets, but also curing both diabetes and renal failure with a single transplant from a living donor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI102405-02
Application #
8725786
Study Section
Special Emphasis Panel (ZAI1-MFH-I (M1))
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$352,009
Indirect Cost
$136,010
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136
Sasaki, Hajime; Oura, Tetsu; Spitzer, Thomas R et al. (2018) Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach. Hum Immunol 79:258-265
Smith, R N; Adam, B A; Rosales, I A et al. (2018) RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant 18:1340-1350
Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27
Smith, R N; Matsunami, M; Adam, B A et al. (2018) RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 18:1328-1339
Benichou, Gilles; Prunevieille, Aurore (2018) Graft-derived exosomes. When small vesicles play a big role in transplant rejection. Am J Transplant 18:1585-1586
Thaiss, Cornelius C; Oura, Tetsu; Sasaki, Hajime et al. (2018) Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates. Transplantation :
Adam, B A; Smith, R N; Rosales, I A et al. (2017) Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes. Am J Transplant 17:2841-2850
Pathiraja, V; Villani, V; Tasaki, M et al. (2017) Tolerance of Vascularized Islet-Kidney Transplants in Rhesus Monkeys. Am J Transplant 17:91-102
Dehnadi, Abbas; Benedict Cosimi, A; Neal Smith, Rex et al. (2017) Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. Nat Commun 8:13899

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