Previous studies in this program project have demonstrated that immune mechanisms play a critical role in the success of allogeneic stem cell transplantation. The previous projects outline a series of clinical and laboratory studies designed to apply new concepts and methods of graft engineering to allogeneic stem cell transplantation. These projects will develop and test novel methods to selective modulate T cell reconstitution in the allogeneic stem cell recipient. In this context, the project will focus on developing a better understanding of the specific targets of allo- immunity in vivo. In previous clinical trials we have demonstrated that infusion of CD4+ donor T cells results in a dramatic and sustained response against relapsed leukemia. This response appears to be directed against antigens expressed on normal as cell as malignant hematopoietic cells, but is not frequently associated with a clinical syndrome of graft-vs. host disease (GVHD). Recent studies in our laboratory have shown that donor lymphocyte infusion (DLI) initiates a complex immune response, resulting in both B cell and T cell immunity against recipient hematopoietic stem cells., but is not frequently associated with a clinical syndrome of graft-vs-host disease (GVHD). Recent studies in our laboratory have shown that donor lymphocyte infusion (DLI) initiates a complex immune response, resulting in both B cell and T cell immunity against recipient hematopoietic sem cells. We have recently identified a series of both B cell and T cell immunity against recipient hematopoietic stem cells. We have recently identified a series of target antigens based on their recognition by specific antibodies after DLI. Thirteen antigens have been cloned using a SEREX approach and further studies in this project will focus on this novel antigens as targets of the immune response against recipient stem cells. As we continue to characterize the role of B cell and T cell responses in selected individual, we hope to develop a better understanding of the relevant target antigens for both GVHD and graft-vs-leukemia (GVL). Working with other investigators in this Program Project, these experiments will lead to the development of new methods for selectively enhancing appropriate responses or selectively abrogating inappropriate responses. These experiments will be carried out in 4 Specific Aims: 1. Characterization of B cell responses specific for defined antigens expressed on recipient hematopoietic stem cells and leukemic stem cells. 2. Identify T cell defined antigens that represent clinically relevant targets for selective elimination of recipient hematopoietic stem cells and residual leukemia cells. 3. Molecular characterization of B and T cell defined antigens in DLI responders. 4. Develop new methods for identifying target antigens associated with GVHD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI029530-10
Application #
6400417
Study Section
Special Emphasis Panel (ZAI1-NBS-I (S1))
Project Start
1990-08-01
Project End
2004-07-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2000
Total Cost
$247,466
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Exley, Mark A; Friedlander, Phillip; Alatrakchi, Nadia et al. (2017) Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial. Clin Cancer Res 23:3510-3519
Matsuoka, Ken-ichi; Koreth, John; Kim, Haesook T et al. (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 5:179ra43
Brown, J R; Kim, H T; Armand, P et al. (2013) Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 27:362-9
Jacobson, Caron A; Turki, Amin T; McDonough, Sean M et al. (2012) Immune reconstitution after double umbilical cord blood stem cell transplantation: comparison with unrelated peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 18:565-74
Kawano, Yutaka; Kim, Haesook T; Matsuoka, Ken-Ichi et al. (2011) Low telomerase activity in CD4+ regulatory T cells in patients with severe chronic GVHD after hematopoietic stem cell transplantation. Blood 118:5021-30
Koreth, John; Matsuoka, Ken-ichi; Kim, Haesook T et al. (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365:2055-66
Schoenfeld, Jonathan D; Dranoff, Glenn (2011) Anti-angiogenesis immunotherapy. Hum Vaccin 7:976-81
Brown, Julia A; Stevenson, Kristen; Kim, Haesook T et al. (2010) Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis. Blood 115:4111-9
Matsuoka, Ken-ichi; Kim, Haesook T; McDonough, Sean et al. (2010) Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest 120:1479-93
Sarantopoulos, Stefanie; Stevenson, Kristen E; Kim, Haesook T et al. (2009) Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 113:3865-74

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