The overall theme of our current proposal is to delineate protocols for the induction and maintenance of donor specific tolerance in recipients of islet allografts, with our ultimate goal being the reversal of insulin dependent diabetes mellitus. We plan to thoroughly investigate three approaches which have yielded promising results in animal models: l)intrathymic inoculation of donor cells and/or antigen, primarily to mediate clonal deletion of anti-donor specific T cells, and 2) intravenous administration of donor bone marrow cells, with the aim of inducing a state of microchimerism and/or recruiting both central and peripheral mechanisms of tolerance, 3) inhibition of costimulatory (B7/CD28/CTLA-4) and adhesive interactions between recipient leukocytes and donor cells or tissues. We will define the mechanism(s) of donor specific tolerance by evaluating in vitro and in vivo immunoreactivity to both donor and 3rd party cells and tissues, and in addition, will search for the presence of chimerism in bone marrow/islet recipients. We will also explore the variables inherent in each protocol by analyzing the type and timing of immunosuppression relative to intrathymic inoculation or i.v. bone marrow infusion. Interference in such pathways, i.e., recognition of donor alloantigen in the absence of the appropriate costimulatory signals, can lead to clonal anergy. Findings from these studies have the potential of directing us towards a multifaceted approach to the induction of donor specific tolerance in humans. In addition, the induction of tolerance to transplanted islets may provide the added benefit of tolerizing a diabetic patient to the grafted islets, thus preventing recurrence of the autoimmune process. The availability of the findings from these studies will provide key insights that will be applied to the refinement of ongoing clinical trials of islet allotransplantation in humans. The application of this information should, as well, be generally applicable to the field of organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025802-17
Application #
2414772
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Harmon, Joan T
Project Start
1980-05-01
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Fotino, Nicoletta; Fotino, Carmen; Pileggi, Antonello (2015) Re-engineering islet cell transplantation. Pharmacol Res 98:76-85
Miki, Atsushi; Ricordi, Camillo; Yamamoto, Toshiyuki et al. (2014) Improved human islet preparations using glucocorticoid and exendin-4. Pancreas 43:1317-22
Ricordi, Camillo (2014) The path for tolerance permissive immunomodulation in islet transplantation. Transplantation 98:1260-1
Pileggi, Antonello; Ricordi, Camillo (2013) A new home for pancreatic islet transplants: the bone marrow. Diabetes 62:3333-5
Fotino, Carmen; Molano, R Damaris; Ricordi, Camillo et al. (2013) Transdisciplinary approach to restore pancreatic islet function. Immunol Res 57:210-21
Pileggi, Antonello; Klein, Dagmar; Fotino, Carmen et al. (2013) MicroRNAs in islet immunobiology and transplantation. Immunol Res 57:185-96
Pileggi, Antonello; Xu, Xiumin; Tan, Jianming et al. (2013) Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant 18:672-81
Khan, Aisha; Jindal, Rahul M; Shriver, Craig et al. (2012) Remote processing of pancreas can restore normal glucose homeostasis in autologous islet transplantation after traumatic whipple pancreatectomy: technical considerations. Cell Transplant 21:1261-7
Pileggi, Antonello (2012) Mesenchymal stem cells for the treatment of diabetes. Diabetes 61:1355-6
Takahashi, Hidenori; Ruiz, Phillip; Ricordi, Camillo et al. (2012) Quantitative in situ analysis of FoxP3+ T regulatory cells on transplant tissue using laser scanning cytometry. Cell Transplant 21:113-25

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