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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1787-1790.
Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-02-0361.
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IMMUNOBIOLOGY
Brief report
Immunomodulatory drug costimulates T cells via the B7-CD28 pathway
Richard LeBlanc,
Teru Hideshima,
Laurence P. Catley,
Reshma Shringarpure,
Renate Burger,
Nicholas Mitsiades,
Constantine Mitsiades,
Puneet Cheema,
Dharminder Chauhan,
Paul G. Richardson,
Kenneth C. Anderson, and
Nikhil C. Munshi
From the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA; and Boston VA Healthcare System, Department of Medicine, Harvard Medical School, Boston, MA.
Although thalidomide (Thal) does not directly induce T-cell activation, it increases proliferation of T cells following CD3 activation. In this study, we examined the immunomodulatory effects of a more potent analog of Thal, immunomodulatory drug (IMiD), on T cells. Although IMiD3 does not directly stimulate proliferation of normal donor CD3+ T cells, it significantly costimulates proliferation of CD3+ T cells induced by CD3 ligation (stimulation index [SI], 2.4), immature dendritic cells (DCs; SI, 2.1), and mature DCs (SI, 2.6). T-cell proliferation triggered by DCs was abrogated by cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA-4–Ig), and IMiD3 partially overcomes this inhibitory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4–Ig on Epstein-Barr virus (EBV) and influenza (Flu)–specific CD4 and CD8 T-cell responses, as measured by cytokine capture and enzyme-linked immunosorbent spot (ELISPOT) assay. IMiD3 did not induce up-regulation of CD28 expression on T cells, or of CD80-CD86 expression on dendritic cells. Importantly, IMiD3 triggers tyrosine phosphorylation of CD28 on T cells, followed by activation of nuclear factor  B (NF-B), a known downstream target of CD28 signaling. These results therefore define the costimulatory mechanism whereby IMiD3 induces T-cell activation and provide the cellular and molecular basis for use of IMiD3 as an adjuvant in immunotherapeutic treatment strategies for multiple myeloma.
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