The cell therapy market had revenue exceeding one billion dollars, with significant growth expected. While autologous cells are ideal to avoid immune rejection, allogeneic sources are attractive for diseases in which autologous cells are not readily available due to disease (e.g., Type 1 Diabetes (T1D)). Allogeneic islet transplantation for the treatment of T1D, which affects an estimated 1.5 million Americans, is an experimental therapy with limited tissue availability, with allogeneic stem cell-derived -cells showing great promise. In the previous funding for this grant, we developed microporous scaffolds to support engraftment of the transplanted islets at a clinically translatable extrahepatc site, and demonstrated the ability to modulate the local environment in order to maximize engraftment of transplanted cells. In this proposal, we investigate the induction of immune tolerance via biomaterials for allogeneic cell donors, which would avoid the long-term use of immunosuppressive drugs. Immunosuppressive drugs are currently used for solid organ and cell transplantation to prevent rejection, which leads to the non-specific immune suppression and may be diabetogenic. We propose a two-pronged approach: i) microporous scaffolds that locally modulate the immune response, and ii) i.v. infused particles delivering tolerogenic allogeneic antigens that systemically modulate the immune response. Our previous funding period supported the development of scaffolds to create an environment that supports islet engraftment, and Aim 1 of this proposal extends those results by locally delivering factors to modulate the immune response. Locally providing anti-inflammatory cytokines, chemokines may redirect immune cells away from an inflammatory phenotype in order to interrupt inflammation at an early stage. Importantly, these cytokines may limit APC activation and migration, which may decrease activation of CD4+ helper and CD8+ killer T cells that are responsible for graft rejection. We anticipate that these scaffolds may reduce the number of islets necessary for transplantation and facilitate tolerance induction by particles carrying donor antigen (Aim 2).
Specific Aim 2 will investigate particle-based modulation of systemic anti-donor adaptive immune response for effective donor-specific tolerance induction for islet transplantation. Preliminary studies have demonstrated the capacity of PLG particles carrying solubilized donor antigens (PLG-dAg). Antigen isolation and loading into the particles will be investigated for their tolerogenic effects on APC function, along with the specificity and stability of transplant tolerance. We hypothesize that functionalized PLG-dAg effectively target and tolerize host APCs, and consequently induce stable and donor-specific transplant tolerance. Taken together, we anticipate that the scaffold microenvironment and antigen-loaded particles can synergize to effectively induce tolerance, which will reduce the number of islets needed for transplantation, and will enable allogeneic transplantation without immunosuppression, which would be a significant advance enabling numerous cell therapies.

Public Health Relevance

Allogeneic cell therapies are promising for the treatment of numerous diseases, yet the allogeneic immune response following transplantation results in tissue rejection unless systemic immunosuppression is employed. We propose a strategy that is based on i) particles loaded with allogeneic antigens combined with ii) immunomodulation at the islet graft as a means to eliminate or reduce the use of immunosuppressive drugs. Successful completion of these studies would identify particles and scaffolds that are novel, safe, efficient and clinically relevant for promoting allogeneic tolerance for therapies in which cell transplantation is being employed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB009910-08
Application #
9302428
Study Section
Special Emphasis Panel (ZRG1-BST-B (02)M)
Program Officer
Hunziker, Rosemarie
Project Start
2010-05-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
8
Fiscal Year
2017
Total Cost
$522,993
Indirect Cost
$90,256
Name
University of Michigan Ann Arbor
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kasputis, Tadas; Clough, Daniel; Noto, Fallon et al. (2018) Microporous Polymer Scaffolds for the Transplantation of Embryonic Stem Cell Derived Pancreatic Progenitors to a Clinically Translatable Site for the Treatment of Type I Diabetes. ACS Biomater Sci Eng 4:1770-1778
Dangi, Anil; Zhang, Lei; Zhang, Xiaomin et al. (2018) Murine CMV induces type 1 IFN that impairs differentiation of MDSCs critical for transplantation tolerance. Blood Adv 2:669-680
Liu, Jeffrey M H; Zhang, Xiaomin; Joe, Shelby et al. (2018) Evaluation of biomaterial scaffold delivery of IL-33 as a localized immunomodulatory agent to support cell transplantation in adipose tissue. J Immunol Regen Med 1:1-12
Skoumal, Michael; Woodward, Kyle B; Zhao, Hong et al. (2018) Localized immune tolerance from FasL-functionalized PLG scaffolds. Biomaterials 192:271-281
Park, Jonghyuck; Decker, Joseph T; Smith, Dominique R et al. (2018) Reducing inflammation through delivery of lentivirus encoding for anti-inflammatory cytokines attenuates neuropathic pain after spinal cord injury. J Control Release 290:88-101
Rios, Peter D; Skoumal, Michael; Liu, Jeffrey et al. (2018) Evaluation of encapsulating and microporous nondegradable hydrogel scaffold designs on islet engraftment in rodent models of diabetes. Biotechnol Bioeng 115:2356-2364
Weaver, Jessica D; Headen, Devon M; Aquart, Jahizreal et al. (2017) Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites. Sci Adv 3:e1700184
Kuo, Robert; Saito, Eiji; Miller, Stephen D et al. (2017) Peptide-Conjugated Nanoparticles Reduce Positive Co-stimulatory Expression and T Cell Activity to Induce Tolerance. Mol Ther 25:1676-1685
Dangi, Anil; Luo, Xunrong (2017) Harnessing Apoptotic Cells for Transplantation Tolerance: Current Status and Future Perspectives. Curr Transplant Rep 4:270-279
Rao, Shreyas S; Bushnell, Grace G; Azarin, Samira M et al. (2016) Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo. Cancer Res 76:5209-18

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