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Acute graft-versus-host disease without costimulation via CD28
D E Speiser1, M F Bachmann, A Shahinian
1Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Transplantation
|April 15, 1997
Summary
Lethal graft-versus-host disease (GVHD) can occur even without CD28 costimulation. This study shows that T lymphocyte activity and acute GVHD develop in CD28-deficient mice, challenging previous assumptions.
Area of Science:
- Immunology
- Transplantation Immunology
Background:
- T lymphocyte activation relies on costimulatory signals, notably CD28 binding to B7-1/B7-2 on antigen-presenting cells.
- CTLA4Ig treatment inhibits graft-versus-host disease (GVHD) by blocking CD28-B7 interactions, suggesting a critical role for CD28.
Purpose of the Study:
- To investigate the specific role of CD28 in the development of acute GVHD using gene-targeted mice.
- To determine if CD28 costimulation is essential for inducing lethal GVHD.
Main Methods:
- Experiments utilized gene-targeted (CD28-deficient) and wild-type mice.
- Allogeneic stimulation models were employed, including strong (H2(b) anti-H2(d)) and weak (H2(d) anti-H2(b)) major histocompatibility complex (MHC) contexts.
- In vitro T-cell cytotoxicity assays and in vivo induction of acute lethal GVHD were assessed.
Main Results:
- CD28-deficient lymphocytes induced efficient in vitro T-cell cytotoxicity.
- Acute lethal GVHD was induced by CD28-deficient lymphocytes in both strong and weak allogeneic stimulation models.
- The onset of GVHD in CD28-deficient mice was only partially delayed compared to wild-type mice.
Conclusions:
- Lethal acute GVHD can develop independently of CD28 costimulation.
- The CD28-B7 pathway is not absolutely required for the induction of lethal GVHD, though it may modulate its kinetics.