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PMID: 12865411 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity.

The Journal of clinical investigation ·Vol. 112 ·No. 2 ·2003-07-00 ·Pages 234-43

Harada H, Salama AD, Sho M, Izawa A, Sandner SE, Ito T, Akiba H, Yagita H, Sharpe AH, Freeman GJ, Sayegh MH

Abstract

Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility-mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility-mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10-producing cells and an increased frequency of both IFN-gamma- and IL-4-producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription-6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.

MeSH Terms
Animals Apoptosis CD28 Antigens/biosynthesis CD4-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/immunology Cytokines/metabolism Enzyme-Linked Immunosorbent Assay Flow Cytometry Graft Rejection Inducible T-Cell Co-Stimulator Ligand Interferon-gamma/metabolism Interleukin-4/metabolism Lymphocyte Activation Mice Mice, Inbred BALB C Mice, Inbred C57BL Proteins/physiology Receptors, Antigen, T-Cell/metabolism STAT6 Transcription Factor Signal Transduction Spleen/cytology T-Lymphocytes/immunology,metabolism Time Factors Trans-Activators/metabolism
Chemicals
CD28 Antigens Cytokines Icosl protein, mouse Inducible T-Cell Co-Stimulator Ligand Proteins Receptors, Antigen, T-Cell STAT6 Transcription Factor Stat6 protein, mouse Trans-Activators Interleukin-4 Interferon-gamma
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Harada Hiroshi
Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Salama Alan D
Sho Masayuki
Izawa Atsushi
Sandner Sigrid E
Ito Toshiro
Akiba Hisaya
Yagita Hideo
Sharpe Arlene H
Freeman Gordon J
Sayegh Mohamed H
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI17008
Published
2003-07-00
Pages
234-43
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC164288
Subset
IM
Grants
NCI NIH HHS · CA84500 · United States
NCI NIH HHS · R01 CA084500 · United States
NIAID NIH HHS · R01 AI051559 · United States
NIAID NIH HHS · P01 AI041521 · United States
NIAID NIH HHS · P01 AI039671 · United States
NIAID NIH HHS · 1R01 AI51559 · United States
NIAID NIH HHS · 5 P01 AI41521 · United States
NIAID NIH HHS · P01 AI39671 · United States
External Links
PubMed source DOI: 10.1172/JCI17008 PMC Full Text View journal details
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