We have identified a new, heretofore undescribed class of lymphocytes with a novel CD4+8-3- phenotype. We find these cells in the skin and spleen of mice with graft versus host disease (GVHD), which is a lethal complication of bone marrow transplantation. Despite advances in immunobiology, our understanding of effector mechanisms of GVHD is unclear. We have developed a murine model of bone marrow transplantation in order to focus on the effector:target interactions during GVHD, particularly in the skin. Our studies demonstrate the presence of a previously unrecognized type of lymphocyte in affected GVHD organs. We have isolated this cell and injected it into the skin of secondary recipients, where it causes the lesion of GVHD skin damage. We have also created CD4+8-3- T cell hybridomas from the spleens of mice with GVHD in order to study these cells in vitro. With these preliminary studies as a basis, we propose to test the hypothesis that CD4+8-3- lymphocytes are important effector cells in GVHD.
Our specific aims are: 1. To characterize critical mechanisms of action of effector cells in the skin during GVHD. 2. To characterize which lymphokines participate in damaging the skin during GVHD. 3. To determine the importance of CD4+8-3- lymphocytes in other models of GVHD. 4. To determine whether CD4+8-3- lymphocytes are of T cell lineage. We expect that insights from these murine models will increase our understanding both of GVHD effector mechanisms and of developmental abnormalities of cell-mediated immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI030018-01A2
Application #
3145070
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-07-01
Project End
1996-04-30
Budget Start
1992-07-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Cooke, K R; Kobzik, L; Martin, T R et al. (1996) An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 88:3230-9
Rimm, I J; Krenger, W; Beland, J L et al. (1996) TCR-beta transgenic mice fail to mediate a GVHR due to defects of allorecognition and subsequent IL-2 generation. Bone Marrow Transplant 17:835-42
Tan, K N; Min, H K; Pan, L et al. (1996) Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. Int Immunol 8:689-99
Krenger, W; Ferrara, J L (1996) Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res 15:50-73
Krenger, W; Falzarano, G; Delmonte Jr, J et al. (1996) Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood 88:1113-21
Falzarano, G; Krenger, W; Snyder, K M et al. (1996) Suppression of B-cell proliferation to lipopolysaccharide is mediated through induction of the nitric oxide pathway by tumor necrosis factor-alpha in mice with acute graft-versus-host disease. Blood 87:2853-60
Krenger, W; Snyder, K M; Byon, J C et al. (1995) Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol 155:585-93
Pan, L; Delmonte Jr, J; Jalonen, C K et al. (1995) Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 86:4422-9
Akhtar, I; Gold, J P; Pan, L Y et al. (1995) CD4+ beta islet cell-reactive T cell clones that suppress autoimmune diabetes in nonobese diabetic mice. J Exp Med 182:87-97
Krenger, W; Snyder, K; Smith, S et al. (1994) Effects of exogenous interleukin-10 in a murine model of graft-versus-host disease to minor histocompatibility antigens. Transplantation 58:1251-7

Showing the most recent 10 out of 15 publications