Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD

Matta, Benjamin M.; Reichenbach, Dawn K.; Zhang, Xiaoli; Mathews, Lisa; Koehn, Brent H.; Dwyer, Gaelen K.; Lott, Jeremy M.; Uhl, Franziska Maria; Pfeifer, Dietmar; Feser, Colby J.; Smith, Michelle J.; Liu, Quan; Zeiser, Robert; Blazar, Bruce R.; Turnquist, Hēth

doi:10.1182/blood-2015-12-684142

Cited by 97 publications

(101 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tcon and Tregs were purified as described. 19 IL-2 (0.5 mg)/JES6-1 anti-IL-2 mAb (25 mg) complexes were injected intraperitoneally days 0-3 (aGVHD) or days 28-56 (cGVHD).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

McDonald-Hyman

Flynn

Panoskaltsis‐Mortari

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• IL-2/mAb complexes expand Tregs and treat established murine cGVHD, but concurrent T-effector cell expansion can reduce their therapeutic index.• Prophylactic Treg infusions can prevent cGVHD, whereas therapeutic efficacy requires homing to and inhibition of the GC reaction.Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. (Blood. 2016;128(7):1013-1017

show abstract

“…Tcon and Tregs were purified as described. 19 IL-2 (0.5 mg)/JES6-1 anti-IL-2 mAb (25 mg) complexes were injected intraperitoneally days 0-3 (aGVHD) or days 28-56 (cGVHD).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

McDonald-Hyman

Flynn

Panoskaltsis‐Mortari

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…As noted above, IL-33 can be classified as an alarmin, and the damaged tissue that releases IL-33 also secretes soluble ST2 (129). However, IL-33 has pleiotropic effects, and administration of IL-33 prior to BMT can drive proliferation of Tregs and ILC2s (our unpublished data) that prevent experimental GVHD (130). Thus, the effect of therapeutic strategies to manipulate the IL-33/ST2 axis in clinical HCT may not be straightforward.…”

Section: Inflammatory Cytokinesmentioning

confidence: 88%

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Ferrara¹,

Smith²,

Sheets³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Acute graft-versus-host disease (aGVHD) was noted as a complication of allogeneic bone marrow (BM) transplantation in animal models more than six decades ago (1, 2). The initial descriptions of aGVHD differentiated it from the complications of BM aplasia and focused on the severe consequences of GVHD for lower gastrointestinal (GI) tract function, as manifested by weight loss and profound diarrhea. Subsequent studies clearly identified donor T cells as the critical cells required for the induction of aGVHD (3)(4)(5). aGVHD was shown to predominantly involve the skin, liver, and lower GI tract and, later, the upper GI tract (6). In the absence of approaches to prevent aGVHD, this complication occurs in close to 100% of recipients of allogeneic BM/stem cell transplants (allogeneic hematopoietic cell transplantation, allo-HCT), greatly limiting the survival of the first cohort of patients who underwent allo-HCT. Lower GI tract GVHD: clinical findingsDespite the use of prophylaxis to prevent aGVHD, without rigorous T cell depletion this complication occurs in 30%-70% of patients undergoing allo-HCT (7-9). Standard treatment of aGVHD is the administration of systemic corticosteroids and additional immunosuppressive agents, which, as primary therapy, do not substantially improve patient outcomes (10). Thirty to seventyfive percent of patients who develop aGVHD will have a complete response to corticosteroid therapy (11).The outcome for patients with severe aGVHD (grades III-IV) of the lower GI tract is poor, with 25% overall survival (12). Four risk factors (corticosteroid resistance, age under 18 years at time of transplant, GI tract bleeding, and total bilirubin greater than 3 mg/dl) were found on multivariate analysis to be statistically associated with poor survival; no patients with all 4 factors survived, highlighting the critical need to improve survival for these patients. This Review will focus on recent findings regarding the homeostatic mechanisms of the lower GI tract that relate to the pathophysiology of aGVHD involving the distal small intestine and colon. Immune homeostasis in the GI tractThe immune balance of the human small intestine and colon is complex. There are over 100 trillion bacteria that are critical to the function of the GI tract, and individuals are exposed to a huge number of food-borne antigens on a daily basis. Thus, there must exist dynamic and robust mechanisms that mediate immune responses to pathogenic organisms but that prevent immune responses to normal flora and dietary antigens.Antigen-presenting cells in the GI tract. Specialized hematopoietic antigen-presenting cells (APCs) in the GI tract include multiple subpopulations of dendritic cells (DCs) and macrophages ( Figure 1). DCs in the lamina propria (LP) and Peyer's patch sample luminal antigens and migrate to regional lymph nodes (LNs) to activate immune responses (13,14). Macrophages are sessile and are the most abundant innate immune cells in the intestine; they maintain homeostasis by phagocytosing microorganisms and apop...

show abstract

“…In contrast to Reichenbach et al (12), Zhang and colleagues found no effect of recombinant IL-33 treatment on GVHD when given during the peri-transplant period (11). Furthermore, in a third study where exogenous IL-33 was dosed prior and subsequent to allo-HCT it resulted in a protective effect, evident by decreased GVHD development and decreased mortality (13). Similarly, in rodent heart transplant models, administration of IL-33 supported allograft survival (14).…”

mentioning

confidence: 86%

Prospects to translate the biology of IL-33 and ST2 during organ transplantation into therapeutics to treat graft-versus-host disease

Scott¹,

Houslay²,

Cohen³

2016

Ann. Transl. Med.

View full text Add to dashboard Cite

Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD

Abstract: Key Points Peri-alloHCT IL-33 delivery prevents acute GVHD through MAPK-dependent expansion of radiation-resistant recipient ST2+ Tregs. IL-33–expanded Tregs regulate myeloid cell differentiation and activation, and limit effector T-cell accumulation in GVHD-target tissue.

Cited by 97 publications

References 75 publications

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Prospects to translate the biology of IL-33 and ST2 during organ transplantation into therapeutics to treat graft-versus-host disease

Contact Info

Product

Resources

About