In this proposal, we hypothesize that limiting inflammatory and thrombotic responses at the graft-host interface after intraportal islet all transplantation will reduce non-immune islet destruction and, thereby, decrease the donor islet mass required to effectively treat insulin-dependent diabetes mellitus. Further, we speculate that inhibiting injury-induced amplification of the innate immune response will improve long-term allograft survival by modulating the adaptive immune response. Specifically, we intend to: (1) Fabricate nanothin conformal polymer films that enhance early engraftment and long-term islet function. Layer-by-layer polymer assembly will be used to fabricate an ultrathin film that presents peptide ligands to ss cells and ECs at the inner film interface, while localizing thrombomodulin (TM) at the outer surface. Both physiochemical and biological properties of the barrier will be defined in vitro and in vivo. The ability of a conformal coating to enhance islet engraftment will be defined using an established allograft (B10?B6) model of intraportal islet transplantation. Should long-term islet survival be increased, the impact of this strategy on T cell programming will be defined using an antigen-specific (Act-mOVA?B6) islet transplant model. (2) Define the capacity of antibody-directed fusion proteins to abrogate thrombin-dependant inflammatory pathways that contribute to islet destruction. In the first phase of these investigations, we plan to assess the capacity of anti-thrombotic fusion proteins based upon TM and tick anticoagulant peptide (TAP) to selectively target activated platelets and limit coagulant responses in vitro and in vivo. The pharmacokinetic profile will be defined, as well as systemic anticoagulant effects. The second phase of these studies will evaluate the ability of these fusion proteins to enhance portal engraftment and late islet survival in a murine B10?B6 allograft model. Should long-term islet survival be increased, the impact of this strategy on T cell programming will be defined using the Act-mOVA?B6 model. (3) Evaluate the capacity of heparan sulfate-mimetic glycopolymers to inhibit inflammatory events that limit islet engraftment and durable islet function. In the first phase of these investigations, we plan to assess the capacity of heparan sulfate-mimetic glycopolymers to competitively inhibit selectin and chemokine binding events in vitro and to define the pharmacokinetic profile in vivo. In the second phase, we will evaluate the ability of this class of glycomimetic to enhance engraftment in a murine B10?B6 allograft model and modulate T cell programming, should late islet survival be increased. In the final phase, the utility of combining complementary anti-inflammatory and anti-thrombotic strategies in islet allotransplantation will be assessed. Relevance of the project to public health: Primary nonfunction and early no immune islet destruction increase donor islet mass required to effectively treat insulin-dependent diabetes mellitus by islet transplantation. We hypothesize that inhibiting inflammatory and thrombotic responses at the graft-host interface will enhance islet engraftment and limit injury-induced amplification of the adaptive immune response with improved long-term allograft survival.

Public Health Relevance

Primary nonfunction and early no immune islet destruction substantially increase donor islet mass required to effectively treat insulin-dependent diabetes mellitus by islet transplantation. We hypothesize that inhibiting inflammatory and thrombotic responses at the graft-host interface will enhance islet engraftment and limit injury-induced amplification of the adaptive immune response with improved long-term allograft survival. The investigations described in this proposal are directed at the design of molecularly engineered systems, including conformal barriers, anti-thrombotic fusion proteins, and heparan sulfate glycomimetics that limit local thrombotic and inflammatory responses and promote islet function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069275-13
Application #
8324021
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Appel, Michael C
Project Start
1999-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$352,009
Indirect Cost
$140,758
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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