Liver allografts are well tolerated, and other solid organ allografts, such as the small intestine and kidney, transplanted concurrently with livers show improved graft outcomes. However, the mechanisms underlying "hepatic tolerance" have yet to be elucidated. Previous data show that liver dendritic cells (DC) can regulate immune responses and have diminished antigen (Ag) presenting and immune stimulatory function compared with those in lymphoid tissue. Recent focus to explain this has been that functional differences between DC subsets including plasmacytoid (p)DC and myeloid (m)DC exist. It has been hypothesized that immature pDC are inherently tolerogenic. Indeed, data from multiple studies show that pDC play a unique and important role in the generation of tolerance. The tolerogenicity of pDC may be further enhanced when exposed to the unique immunosuppressive microenvironment of the liver, generating immunoregulatory hepatic DC (HDC) that impair induction of (alloreactive) T cells (3). Indeed, a recent paper examining patients who are rejecting small intestine transplant have a higher ratio of mDC to pDC, supporting a tolerogenic role for pDC (4). Little is currently known about the role of DC in small intestine transplant. This work proposes to investigate properties of hepatic and small intestine pDC to elucidate a mechanism by which pDC induce tolerance. Utilizing flow cytometry, reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, mixed leukocyte reaction and T cell suppression assays, we propose in our Aims to elucidate a mechanism by which hepatic pDC induce tolerance, whether by T cell apoptosis and/or the generation of T regulatory cells. We will further examine how small intestinal transplantation alone alters immune regulatory properties. In our final Aim, we will utilize hepatic pDC as cellular therapy in a novel murine model of small intestine transplant to induce Ag specific tolerance. The models and techniques to perform the proposed studies are currently in place in the sponsor's laboratory, making the proposed Aims immediately feasible. Hepatic pDC have the potential to induce Ag specific tolerance in transplant models. By utilizing antigen specific cellular therapy, we have the potential to transform the outcome and management of organ transplantation.

Public Health Relevance

Liver transplants are well tolerated, and other solid organ transplants, such as the small intestine and kidneys, transplanted concurrently with livers show improved graft outcomes. Specific immune cells have been implicated in the ability to induce tolerance. The ability to induce tolerance in transplant patients could significantly improve graft rejection, survival, and patient quality of life outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK094548-03
Application #
8585057
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O1))
Program Officer
Podskalny, Judith M,
Project Start
2012-01-02
Project End
2015-01-01
Budget Start
2014-01-02
Budget End
2015-01-01
Support Year
3
Fiscal Year
2014
Total Cost
$62,030
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143