Allogeneic hematopoietic cell transplant (AlloHCT) is used to treat cancer and is proposed as a method to achieve donor-specific tolerance after organ transplantation. Inducing tolerance to an allogeneic transplant (Tx) would alleviate the need for immunosuppressants, which prevent Tx rapid rejection by globally blunting host immune responses. Unfortunately, these drugs promote infection, cancer, and kidney damage, and fail to prevent chronic rejection, a progressive alloimmune-driven fibrotic process that culminates in Tx dysfunction and failure. The use of AlloHCT for Tx tolerance is limited by the potential for graft-versus-host disease (GVHD), an often fatal condition where donor immune cells attack the host tissues. Thus far, AlloHCT protocols have failed to induce durable tolerance in patients. To address these CLINICAL PROBLEMS, innovation in recipient treatment is needed, and our OBJECTIVE is to use cutting-edge transgenic mouse models to establish the means to eliminate GVHD risks and provide an immunological environment supporting robust Tx-specific tolerance induction. To create space for donor stem cells and prevent their rapid rejection by host immune cells, AlloHCT protocols remove recipient immune and bone marrow cells with harsh conditioning regimens involving total body irradiation (TBI) or chemotherapy. These treatments unavoidably cause tissue damage releasing alarmins, or self-derived immunomodulatory molecules that activate the cells of the immune system. Interleukin (IL)-33 is a proposed alarmin and epithelial cell-derived cytokine, which may drive GVHD and modulate tolerance after AlloHCT. Our preliminary data reveal that conditioning regimens augment IL-33 in GVHD-target tissue and IL-33-stimulated alloreactive donor T cells mediate GVHD. We also demonstrate that preconditioning of AlloHCT recipients with IL-33 before TBI paradoxically protects against GVHD development. These data are consistent with pleiotropic functions of IL-33, which can promote both Type 1 and Type 2 pro-inflammatory responses, but also expand suppressive regulatory T cells. We HYPOTHESIZE that the pleiotropic functions of molecules like IL-33 can be precisely controlled to shape alloimmunity. To precisely control IL-33, we must identify the mechanisms modulating IL-33 expression, release, and promotion of alloimmunity after AlloHCT (AIM 1). We will also assess if countering proposed drivers of IL-33 pro-inflammatory properties after AlloHCT will prevent GVHD and promote Tx tolerance (AIM 2). The proposed studies are INNOVATIVE because they could establish a new paradigm in transplantation where pleiotropic immune stimuli are freed to support tolerance by countering their pro-inflammatory triggers or augmenting their regulatory properties. These studies are SIGNIFICANT, as they will increase our understanding of IL-33 functions in GVHD and may eliminate it as a potential risk factor following AlloHCT. AlloHCT-induced tolerance would eliminate chronic rejection and immunosuppressant-related side effects, thus turning solid organ Tx into a life saving, not just a life extending procedure for end-stage organ failure patients.

Public Health Relevance

Clinical implementation of allogeneic hematopoietic cell transplantation (AlloHCT) for transplant tolerance remains problematic due to host complications, particularly graft-versus-host disease (GVHD), and the failure of AlloHCT to consistently induce durable tolerance. Our proposal aims to elucidate how multi-functional cell signaling molecules, released from host tissue damaged during conditioning before AlloHCT, can be manipulated to prevent GVHD or harnessed to support transplant tolerance. The findings generated by these studies will allow safer and more effective application of AlloHCT for tolerance induction, which would remove the need for life- long delivery of toxic immunosuppressants and improve long-term outcomes after solid organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI121981-02
Application #
9247754
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Nabavi, Nasrin N
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yazdani, Hamza O; Chen, Hui-Wei; Tohme, Samer et al. (2017) IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation. J Hepatol :
Matta, B M; Reichenbach, D K; Blazar, B R et al. (2017) Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses. Am J Transplant 17:320-327
Liew, Foo Yew; Girard, Jean-Philippe; Turnquist, Heth Roderick (2016) Interleukin-33 in health and disease. Nat Rev Immunol 16:676-689
Turnquist, Heth R; Thomson, Angus W (2016) Identity Crisis. Transplantation 100:258-9
Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli et al. (2016) Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128:427-39