Our long-term goal is to develop strategies to prevent and treat chronic graft-versus-host disease (cGVHD) using murine preclinical models. cGVHD has emerged as one of the primary causes of morbidity and mortality following allogeneic HSCT. Whereas acute GVHD rates have decreased with more intensive GVHD preventive agents and use of umbilical cord blood as a source of donor cells, significant cGVHD rates unexpectedly have remained largely unchanged. Moreover, peripheral blood stem cell grafts have been associated with an increased overall risk of cGVHD. As such, cGVHD has emerged as one of the primary causes of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Unfortunately and in rather striking contrast to aGVHD, little progress has been made in cGVHD prevention and therapy. We have generated a bona fide cGVHD model of bronchiolitis obliterans (BO) using cyclophosphamide and total body irradiation. Because cGVHD has a later onset than typical aGVHD, a lower T cell number was infused to permit long-term and continued antigenic stimulation of donor anti-host alloreactive T cells. BO was convincingly demonstrated at late times by multiple parameters including obstructive disease with fibrosis and restrictive lung dysfunction by pulmonary function tests. BO mice had skin, salivary gland, hepatic, and intestinal cGVHD. In contrast to aGVHD, B cells were present in multiple organs including the lung and low serum anti-host alloAb levels were present.
Two specific aims are proposed.
Aim 1 : To define the critical factors and mechanisms responsible for multiorgan system cGVHD and BO generation.
Aim 2. To devise new interventional strategies to prevent or treat early manifestations of cGVHD with BO. We hypothesize that these prophylactic and early therapeutic interventional approaches will be effective in reducing the severity of BO and cGVHD if given prior to the onset of severe fibroproliferative disease.

Public Health Relevance

Benefits. Our goal is to develop clinically relevant approaches to prevent and treat cGVHD which is a major source of moribity and mortality post-transplant, limiting the more widespread use of this methodology for the treatment of malignant and non-malignant disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142106-10
Application #
8468135
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$355,311
Indirect Cost
$121,868
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Borges, Christopher M; Reichenbach, Dawn K; Kim, Beom Seok et al. (2016) Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival. Transpl Int 29:930-40
Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele et al. (2016) The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol 173:96-104
Alho, Ana C; Kim, Haesook T; Chammas, Marie J et al. (2016) Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127:646-57
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; 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
Kim, Haesook T; Zhang, Mei-Jie; Woolfrey, Ann E et al. (2016) Donor and recipient sex in allogeneic stem cell transplantation: what really matters. Haematologica 101:1260-1266
Souroullas, George P; Jeck, William R; Parker, Joel S et al. (2016) An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22:632-40
Koreth, John; Kim, Haesook T; Jones, Kyle T et al. (2016) Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 128:130-7
Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye et al. (2016) Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI Insight 1:e89278

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