Novel therapies to modulate the inflammatory alloresponse in renal grafts (CTOT-21)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date11/1/186/30/20

Funding

  • University of California, San Francisco (11156sc//U01AI113362)
  • National Institute of Allergy and Infectious Diseases (11156sc//U01AI113362)

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