Minor histocompatibility antigens (mHA) are peptides derived from normal cellular proteins presented by major histocompatibility complex (MHC) class I and class II molecules. Following allogeneic hematopoietic stem cell transplantation (HSCT), recipient mHA are recognized by donor T cells and become the primary targets of graft-vs-host disease (GVHD). To the extent that mHA are expressed on leukemia cells, these antigens also become important targets of graft-vs-leukemia (GVL) following HSCT. Several well-defined mHA are encoded by genes on the Y chromosome, and CD4+ and CD8+ T cell responses to HY antigens following allogeneic HSCT can mediate GVHD and GVL. Using HY proteins as a model for human mHA, previous laboratory studies in this project demonstrated that male patients engrafted with stem cells from female donors frequently develop antibodies that recognize Y-encoded proteins after transplant. HY antibodies typically develop 4-8 months after transplant and do not occur in patients who receive stem cells from gender-matched donors. HY antibodies persist at high titer for prolonged periods and are significantly associated with the development of chronic GVHD. In studies described in Project 1, these observations led to the evaluation of B cell directed therapy with rituximab for patients with steroid resistant chronic GVHD with promising clinical results. Although these observations suggest that antibodies specific for mHA play a role in chronic GVHD, the mechanisms whereby HY antibodies contribute to tissue damage in affected organs have not been elucidated. To better define the role of B cells and antibodies in the pathogenesis of chronic GVHD, proposed studies in Project 3 will develop new genomic and proteomic approaches to define the spectrum of antibody targets in patients with chronic GVHD and to identify clinically relevant new mHA. Proposed studies will also examine B Cell Activating Factor (BAFF) as a potential biologically relevant marker of chronic GVHD and define the mechanisms whereby B cells and antibodies interact with T cells and contribute to GVHD and GVL following HSCT. There are 4 Specific Aims in Project 3. 1 .Define the spectrum of B cell target antigens in patients with chronic GVHD. 2. Identify novel mHA through genomic comparisons of HLA-identical recipients and donors. 3. Determine whether soluble BAFF levels accurately predict the development of chronic GVHD. 4. Define the mechanisms whereby B cells and antibodies contribute to the development of tissue damage following allogeneic HSCT.

Public Health Relevance

Acute and chronic GVHD result from recognition of recipient cells by donor immune cells after allogeneic HSCT. Although GVHD occurs frequently and leads to substantial toxicity, few specific antigenic targets have been identified. Previous studies in this project demonstrated that both donor B cells and T cells contribute to chronic GVHD. Studies proposed in this project will develop new methods to identify specific targets of donor B and T cells and will determine how these cells cooperate to cause tissue injury.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA142106-10
Application #
8468137
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
$283,037
Indirect Cost
$97,078
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

Showing the most recent 10 out of 161 publications