CD28-specific antibody prevents graft-versus-host disease in mice

XZ Yu, SJ Bidwell, PJ Martin… - The Journal of Immunology, 2000 - journals.aai.org
XZ Yu, SJ Bidwell, PJ Martin, C Anasetti
The Journal of Immunology, 2000journals.aai.org
The costimulatory molecules B7-1 and B7-2 regulate T cell activation by delivering activation
signals through CD28 and inhibitory signals through CTLA4. Graft-vs-host disease (GVHD)
is caused by activated donor T cells. Previously, we showed that CD28-deficient donor T
cells induced less-severe GVHD than wild-type donor T cells, suggesting that CD28 signals
exacerbate GVHD. In this paper we demonstrate that CTLA4 signals attenuate the severity of
GVHD. Targeting the CD28 receptor with a specific mAb modulates the receptor in vivo …
Abstract
The costimulatory molecules B7-1 and B7-2 regulate T cell activation by delivering activation signals through CD28 and inhibitory signals through CTLA4. Graft-vs-host disease (GVHD) is caused by activated donor T cells. Previously, we showed that CD28-deficient donor T cells induced less-severe GVHD than wild-type donor T cells, suggesting that CD28 signals exacerbate GVHD. In this paper we demonstrate that CTLA4 signals attenuate the severity of GVHD. Targeting the CD28 receptor with a specific mAb modulates the receptor in vivo, inhibits donor T cell expansion, and prevents GVHD. CTLA4 signaling was necessary for this effect because treatment with a soluble ligand that blocks binding of B7 to both CD28 and CTLA4 did not prevent GVHD as effectively as anti-CD28 mAb. These results support the current model of T cell costimulation in which CD28 signals amplify GVHD while CTLA4 signals inhibit GVHD, providing evidence that selective targeting of CD28 might be a better therapeutic strategy for inducing immunological tolerance than blocking the ligands for both CD28 and CTLA4.
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