Thymic-derived CD4+25+FoxP3+ regulatory T cells (Tregs) are required to suppress autoimmunity and limit foreign antigen responses. Our first-in-human phase I dose escalation trial of ex vivo expanded human Tregs proved efficacious in significantly reducing the incidence of acute graft-vs-host disease (GVHD). Two major limitations to uniform efficacy were identified: Problem 1 (achieving optimal suppression): The %suppression was variable. Problem 2 (maintaining adequate Treg:Teffector ratios): Ratios of 1:5.5 achieved were well below the desired ratios of e1:1 need for GVHD prevention in mice;no Tregs were detected by 2 weeks post-transfer.
Aim 1 will focus on Problem 1. PKC-q coordinates immune function, which results in its movement to the immunological synapse (direct contact point between T cell and antigen-presenting cell) in Teffectors but not Tregs. PKC-q deficient murine Teffectors are unable to cause GVHD but can retain anti-tumor and anti- pathogen responses. Tregs treated with a small molecule PKC-q inhibitor had augmented suppressor function and were more effective in suppressing murine colitis.
In aim 1, focused on Problem 1, we will use small molecule PKC-q inhibitors in vitro or in vivo to test the hypotheses that murine and human Treg potency for GVHD suppression is limited by movement of PKC-q into the immunological synapse.
In aim 2, focused on Problem 2, we will test the hypothesis that sustained IL-2R signaling pathways will provide a PKC- q independent route to Treg expansion and GVHD suppression. We will use 3 strategies to improve Treg mediated GVHD suppression: (a) administer IL-2/anti-IL2 antibody complexes or low dose IL-2 to preferentially expand murine and human Tregs vs Teffectors;(b) Constitutively express STAT5b in murine and human Tregs based upon our findings that constitutive STAT5b promotes murine Treg generation, proliferation and function including GVHD suppression, bypassing the need for IL-2, present in limiting amounts in vivo;and (c) increase b-catenin signaling using a GSK-3b inhibitor in vitro or expressing a stabilized b-catenin in human Tregs since stabilized b-catenin reduces Treg dependency upon IL-2 and provides a marked enhancement of murine Treg survival and efficacy in preventing colitis.
In aim 3, we will select the best 1-2 approaches, derived from studies in aims 1 and 2, for testing in preclinical GVHD models for the preservation of beneficial immune responses later post-transplant. Long-term chimeras that do not succumb to GVHD lethality, as a result of preferred approaches developed aims 1 and 2, will be challenged with leukemia cells or bacterial or viral pathogens to quantify the extent to which the immune system can respond to life-threatening complications post-transplant.

Public Health Relevance

Our team of experts will develop novel approaches and gain biological insights into Tregs. Our findings will have broad implications for the use of Tregs in controlling adverse immune responses by focusing on translational applications to harness the full power of Tregs for hematopoietic stem cell and solid transplantation as well as autoimmunity settings.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL118979-01A1
Application #
8690244
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Di Fronzo, Nancy L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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McKenna Jr, David H; Sumstad, Darin; Kadidlo, Diane M et al. (2016) Optimization of cGMP purification and expansion of umbilical cord blood-derived T-regulatory cells in support of first-in-human clinical trials. Cytotherapy :
Zheng, H B; Watkins, B; Tkachev, V et al. (2016) The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. Am J Transplant :
Le Texier, Laëtitia; Lineburg, Katie E; Cao, Benjamin et al. (2016) Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease. JCI Insight 1:e86850
Schönle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Zeiser, Robert; Socié, Gerard; Blazar, Bruce R (2016) Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol 175:191-207
MacDonald, Kelli P A; Hill, Geoffrey R; Blazar, Bruce R (2016) Chronic graft-versus-host disease: biological insights from pre-clinical and clinical studies. Blood :
Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26
Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L et al. (2016) miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency. Blood 128:1424-35

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