Background: During allogeneic hematopoietic cell transplantation (alloHCT), non-hematopoietic cell IL-33 is augmented and released by recipient conditioning to promote Type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident pro-inflammatory stimuli. We tested if administration of IL-33 before alloHCT or "peri-alloHCT IL-33" could protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms.

Methods: For GVHD studies, recipient mice received repeated injections of recombinant IL-33 before total body irradiation (TBI) and alloHCT (bone marrow +/- T cells). Survival, clinical score, and weight were monitored. Changes in immune cell compartments were assessed by flow cytometry and the capacity of regulatory populations to suppress T cell proliferation was verified ex vivo. In related GVHD studies, recipient Treg were depleted from Foxp3-diphtheria toxin receptor (Foxp3^DTR) mice by delivering DT concurrently with IL-33 administration.

Results: IL-33 administration doubled recipient regulatory T cells (Treg) and increased suppressive myeloid cells, both of which persist following TBI. Importantly, peri-alloHCT delivery of IL-33 resulted in protection against lethal acute GVHD in the majority of recipients. ST2 expression is not exclusive to Treg and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3⁺ cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded recipient Treg were required for protection from GVHD by controlling macrophage activation and preventing accumulation of CD4⁺ and CD8⁺ effector T cells in GVHD target tissue

Conclusions: We demonstrate a protective capacity for peri-alloHCT administration of IL-33 and IL-33-responsive Treg in mouse models of acute GVHD. These findings provide strong support for the concept that the immunoregulatory relationship between IL-33 and Treg can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or induction of solid organ transplantation tolerance.

CITATION INFORMATION: Matta B, Reichenbach D, Zhang X, Koehn B, Mathews L, Feser C, Smith M, Liu Q, Zeiser R, Blazar B, Turnquist H. Administration of IL-33 Before Allogeneic Stem Cell Transplantation Expands Recipient Treg That Prevent Graft- vs. Host Disease. Am J Transplant. 2016;16 (suppl 3).

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