Faculty Collaboration Database

Role of CD28 in acute graft-versus-host disease. Blood 1998 Oct 15;92(8):2963-70

Date

10/09/1998

Pubmed ID

9763584

DOI

10.1182/blood.v92.8.2963

Scopus ID

2-s2.0-0032532609 (requires institutional sign-in at Scopus site)   58 Citations

Abstract

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28(-/-) T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28(+/+) T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28(-/-) or CD28(+/+) splenocytes from B6 mice were transplanted into unirradiated (B6 x DBA/2)F1 (BDF1) recipients. Unlike CD28(+/+), CD28(-/-) T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 x 10(7) CD28(-/-) CD8(+) cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 x 10(5) CD28(+/+) CD8(+) T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8(+) cells helps to eliminate host immunity. Two million CD4(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 x bm12)F1 recipients. With CD28(-/-) cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28(+/+) cells (P < .001). Two million CD8(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 x bm1) F1 recipients. With CD28(-/-) cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28(+/+) cells (P < . 001). (B6 x bm12)F1 and (B6 x bm1)F1 mice surviving after transplantation of CD28(-/-) cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes.

Author List

Yu XZ, Martin PJ, Anasetti C

Author

Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Disease
Animals
CD28 Antigens
CD4-Positive T-Lymphocytes
Graft vs Host Disease
Humans
Interleukin-2
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Radiation Chimera
T-Lymphocytes, Cytotoxic