Solid organ transplantation is an effective therapy for several end-stage diseases. Its success has been driven by the development of immune suppressive medications that impair the immune response to the transplant. To avoid transplant rejection, combinations of these medications must be taken regularly. However, these medications induce undesirable side effects, such as hypertension and diabetes, as well as increased susceptibility to opportunistic infections and cancer. The development of drug delivery platforms that effectively deliver combination immune suppressants while avoiding drug-induced side effects would be transformative for the solid organ transplant field. We hypothesize that co-encapsulation of the commonly employed immune suppressive medications rapamycin and mycophenolic acid into FDA- approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles will prolong allograft survival and avoid the toxic side effects of the soluble administered drugs. In addition, one of our recent studies demonstrated that nanoparticles encapsulated with mycophenolic acid target dendritic cells and induce the upregulation of PD-L1, a negative costimulatory ligand, on these cells. As soluble administered rapamycin is known to impair the upregulation of activating costimulatory ligands on dendritic cells, we also hypothesize that co- encapsulation of rapamycin and mycophenolic acid will induce a pro immune tolerant phenotype in dendritic cells and enhance the development of transplant tolerance. To investigate whether combined encapsulation of rapamycin and mycophenolic acid within nanoparticles prolongs allograft survival, avoids toxic drug side effects and enhances the development of transplant tolerance, we will employ experimental murine transplant models after proof-of-concept studies have been completed in vitro, and both agents have been optimized for NP drug delivery. We expect that the anticipated results of our study will lay the foundation to a ground-breaking clinical study to deliver combination immune suppressants to organ transplant recipients via nanoparticles, which would be transformative to the solid organ transplant field.

Public Health Relevance

Solid organ transplantation is an effective therapy for end-stage diseases but the combination immune suppressants that patients must take to avoid transplant rejection induce side effects and impair clearance of infections and tumor cells. We propose to encapsulate combined immune suppressants within nanoparticles to effectively deliver immune suppression to organ transplant recipients and avoid drug toxicity in mice. Our experimental approach will lay the ground-work for a clinical study that could be transformative for the organ transplant field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI101918-01A1
Application #
8445528
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Nabavi, Nasrin N
Project Start
2013-01-18
Project End
2014-12-31
Budget Start
2013-01-18
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$195,870
Indirect Cost
$70,870
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Look, Michael; Saltzman, W Mark; Craft, Joe et al. (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35:1089-95
Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67
Mori, Daniel N; Kreisel, Daniel; Fullerton, James N et al. (2014) Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 258:132-44
Shen, Hua; Kreisel, Daniel; Goldstein, Daniel Robert (2013) Processes of sterile inflammation. J Immunol 191:2857-63