An important cause of late graft loss is the development of subclinical alloresponses that ultimately injure the graft irreversibly. Inflammation is commonly seen in protocol biopsies of stably functioning grafts and is associated with progressive renal dysfunction. Therapeutic targeting of inflammation in stable grafts with novel agents/approaches has several advantages: (1) reverse the gradual deterioration of renal function and prevent graft loss;(2) provide a practical, safe and more precise model to test the efficacy of new therapies. The concept underlying our proposal is the control the inflammatory alloresponses in the graft through harnessing the regulatory mechanisms of the immune system. We propose to increase the number and/or activity of regulatory T cells (Tregs) by either the infusion of ex vivo expanded Tregs or by inhibiting the IL6 pathway to expand the Treg network. The trials will be performed in transplant recipients who undergo protocol biopsies at 6 months. We propose two studies: a trial of infusions of ex vivo expanded Tregs (TASK) and a trial with tocilizumab, a humanized anti-IL6 receptor antibody (TRAIL).
The aim of the TASK trial is to test the safety and potential efficacy of infused ex vivo expanded polyclonal (poly) or donor (antigen) specific (dar) Tregs vs. controls (no additional therapy) in grafts with cellular inflammation. Deuterium-labeled Tregs allow detection of the infused Tregs in both the circulation and the renal allograft. Additional mechanistic studie including gene expression profiling of blood and kidney as well as analysis of urine cytokines may provide robust efficacy signals. This trial will allow us to make 3 important observations: (1) determine the safety of the infusion of Tregs in kidney transplant recipients;(2) determine if infused Treg (poly or dar) reduce cellular inflammation in the graft and (3) determine if darTregs are superior to polyTregs (clinically or mechanistically). The second study proposes the use of tocilizumab to control inflammation and borderline rejection by Banff criteria by decreasing alloreactive T cells (including TH17cells) and increasing the number and/or activity of Tregs. Patients who have subclinical borderline rejection (currently untreated) in the 6-month biopsy will be randomized to either standard of care (no therapy) or treatment with biweekly subcutaneous injection of tocilizumab for 6 months. A unique and novel aspect of this trial is the introduction of molecular-based personalized medicine: patients with borderline rejection will be stratified for therapy based on a molecular common rejection module score derived from analysis of the kidney biopsy. Follow up renal histology, renal function and mechanistic studies will provide data on the safety and efficacy of this approach. These new therapies may provide a better understanding of the immune mechanisms of rejection and tolerance and thereby lead us to novel and less toxic regimens that can prolong patient and graft survival.

Public Health Relevance

The aim of the proposed clinical trial is to utilize novel therapies to reduce inflammation in the transplanted kidneys by increasing the function and/or number of regulatory T cells that can then control the adverse immune response against the transplanted organ. The relevance of these trials is that enhancing the power of the body's immune system to regulate its response to a transplanted organ may result in better acceptance of the foreign organ and reduce the need to use the current toxic immunosuppressive drugs that shorten the lives of the patients and impact their quality of life.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI113362-01
Application #
8773898
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Hayes, Deborah
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Delville, Marianne; Sigdel, Tara K; Wei, Changli et al. (2014) A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6:256ra136