Graft-versus-host disease (GVHD) limits the application of allogeneic bone marrow transplantation (BMT), a curative therapy for many hematological malignancies and inherited diseases. GVHD, when refractory to its first line therapy, steroids, leads to >70% mortality. A multitude of strategies have been tried to treat steroid refractory GVHD, but as yet the outcomes remain uniformly fatal. Current understanding of the biology indicates that GVHD severity is determined by the balance between cytopathic T effector cells (Teffs) and the cytoprotective regulatory T cells (Tregs) and that this balance is critically dependent on the level of inflammation. We recently demonstrated that human alpha1-antitrypsin (AAT), the major serum serine- protease inhibitor possesses, anti-inflammatory effects that were heretofore largely unrecognized. We have recently shown that AAT reduced several pro-inflammatory cytokines, positively modulated the Teff:Treg balance, prevented and treated GVHD in multiple murine models (PNAS, 2012). But the molecular mechanisms remain unknown. Preliminary data generated by us demonstrate a novel role for sialic acid- binding immunoglobulin-like lectins-G (Siglec-G), on host cells in mitigating GVHD (Blood, 2014). Unpublished preliminary data further suggest that Siglec-G is critical for the anti-inflammatory effects of AAT. In this proposal we will build on these exciting data to translate these observations into a proof of concept, first in human BMT clinical trial under an IND from FDA and meld it with further exploration of the molecular mechanisms of AAT mediated effects. The translational trial has recently been launched to assess the safety and efficacy of AAT in patients with steroid refractory GVHD (already accrued eight patients). Collectively, if successful, our proposal will lead to the development of an entirely novel therapeutic strategy while simultaneously providing novel biological insights into a fatal condition, steroid refractory GVHD.
The specific aims (SA) of the proposal are: SA 1: Elucidate the cellular and molecular mechanisms of AAT mediated regulation of inflammation. In this SA we will test the hypothesis that binding of AAT to the inhibitory Siglec-G receptors is critical for regulating inflammation an the Teff-Tregs balance. SA 2: Perform a pilot clinical trial to determine whether administration of AAT to patients with steroid refractory GVHD will improve response rates. We will explore the hypothesis that administration of AAT will improve the response rates by day 28 in patients that are refractory to steroids GVHD.

Public Health Relevance

Allogeneic hematopoietic or bone marrow transplantation (BMT) is curative therapy against many hematological cancers and diseases. Its applicability has been limited by the toxicity from graft-versus-host disease (GVHD), which results in severe mortality and morbidity. Thus it is large unmet clinical need. We recently demonstrated that a particular protein that is naturally made and present in all patients, alpha 1- antitrypsin (AAT), when supplemented, mitigates inflammation and reduces GVHD in preclinical experimental models. These exciting pre-clinical experimental data form the rationale for our proposal. In a series of complementary studies, we propose to (a) further understand the biological mechanisms of AAT mediated effects and (b) translate the lab observations into a proof-of-concept clinical trial under an IND from FDA. The studies in this proposal, if successful, will lea to the development of an entirely novel strategy for treatment of GVHD and improve outcomes after allogeneic BMT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128046-02
Application #
9036440
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Welniak, Lisbeth A
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Toubai, Tomomi; Rossi, Corinne; Tawara, Isao et al. (2018) Murine Models of Steroid Refractory Graft-versus-Host Disease. Sci Rep 8:12475
Magenau, John M; Goldstein, Steven C; Peltier, Dan et al. (2018) ?1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood 131:1372-1379
Toubai, Tomomi; Tamaki, Hiroya; Peltier, Daniel C et al. (2018) Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation. J Immunol 201:3443-3455
Peltier, Daniel; Reddy, Pavan (2018) Non-Coding RNA Mediated Regulation of Allogeneic T Cell Responses After Hematopoietic Transplantation. Front Immunol 9:1110
Nieves, Evelyn C; Toubai, Tomomi; Peltier, Daniel C et al. (2017) STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity. Biol Blood Marrow Transplant 23:1622-1630
Wu, Shin-Rong; Reddy, Pavan (2017) Regulating Damage from Sterile Inflammation: A Tale of Two Tolerances. Trends Immunol 38:231-235
Toubai, Tomomi; Rossi, Corinne; Oravecz-Wilson, Katherine et al. (2017) Siglec-G represses DAMP-mediated effects on T cells. JCI Insight 2:
Wu, Shin-Rong; Reddy, Pavan (2017) Tissue tolerance: a distinct concept to control acute GVHD severity. Blood 129:1747-1752
Wu, S Julia; Niknafs, Yashar S; Kim, Stephanie H et al. (2017) A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation. Cell Rep 19:2645-2656
Sun, Yaping; Iyer, Matthew; McEachin, Richard et al. (2017) Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells. J Innate Immun 9:126-144

Showing the most recent 10 out of 14 publications