The goal of this study is to determine the role of cytokines in acute graft-versus-host disease (GVHD) following human marrow transplantation. Acute GVHD is a serious complication that kills roughly one-fourth of the 30-50% of patients who develop it. Furthermore, acute GVHD predisposes to the development of chronic GVHD, another major posttransplant complication. Knowledge of the relationship of patient TNF levels to GVHD will be used to improve early diagnosis and to develop preventive and early intervention therapies that are based on TNF neutralization. Preliminary studies have shown that 1) the presence of serum tumor necrosis factor alpha (TNF) and acute GVHD correlate and that 2) TNF inhibits basal keratinocyte proliferation.
Specific aims of this study test the hypothesis that cutaneous GVHD is caused by the cytostatic action of TNF on basal keratinocytes.
The aims ask the following questions. 1) Can pilot data linking serum TNF to GVHD can be confirmed? 2) Do serum TNF levels increase before or after clinical GVHD? Do they predict GVHD? 3) Do serum TNF levels predict or parallel GVHD severity? 4) Do serum TNF levels predict the outcome of GVHD treatment? 5) Are serum TNF levels linked to infection/gut contamination? 6) Does serum TNF correlate with known GVHD risk factors? 7) Is TNF in patient sera cytostatic for basal keratinocytes in vitro? 8) Is keratinocyte growth inhibited by cutaneous GVHD? 9) Do infiltrating lymphocytes inhibit keratinocyte growth? Immuno- and bioassays will be used to assess levels of TNF in serial serum samples drawn 7 to 35 days after marrow transplantation. These results and selected clinical data will be stored in a computerized database and analyzed statistically to answer questions 1-6. Sera and TNF at levels measured therein will be tested for their cytostatic/cytopathic effects in vitro to answer question 7. Evidence that GVHD leads to cytostasis (question 8) will be sought by determining the cell-cycle profiles of keratinocytes in epidermal biopsies. Finally, local tissue levels of TNF will be assessed in freshly isolated epidermal blister fluids and skin-infiltrating cells. The same patient sera and experimental approach can be used to analyze the role of other effector cytokines, such as IF-gamma and lymphotoxin, in acute GVHD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29AI028523-03
Application #
3455271
Study Section
Immunobiology Study Section (IMB)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Koelle, D M; Tigges, M A; Burke, R L et al. (1993) Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes. J Clin Invest 91:961-8
Symington, F W; Brady, W; Linsley, P S (1993) Expression and function of B7 on human epidermal Langerhans cells. J Immunol 150:1286-95
Symington, F W; Holmes, E H; Symington, B E (1992) Human epidermal keratinocyte expression of sialyl-Lewis X. J Invest Dermatol 99:601-7
Symington, F W; Symington, B E; Liu, P Y et al. (1992) The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation. Transplantation 54:457-62
Symington, F W; Santos, E B (1991) Lysis of human keratinocytes by allogeneic HLA class I-specific cytotoxic T cells. Keratinocyte ICAM-1 (CD54) and T cell LFA-1 (CD11a/CD18) mediate enhanced lysis of IFN-gamma-treated keratinocytes. J Immunol 146:2169-75
Symington, F W; Santos, E B (1991) Lysis of keratinocytes by IL-2-activated peripheral blood lymphocytes. J Invest Dermatol 96:127-33
Symington, F W; Santos, E B (1990) Recognition of keratinocytes by cytotoxic T cells specific for conventional HLA class-I alloantigen. J Invest Dermatol 95:224-8
Symington, F W; Pepe, M S; Chen, A B et al. (1990) Serum tumor necrosis factor alpha associated with acute graft-versus-host disease in humans. Transplantation 50:518-21
Symington, B E; Symington, F W (1990) Evidence for phosphatidylinositol-linked forms of human and avian fibronectin receptors. J Biol Chem 265:14069-72