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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-02-0361.
Submitted February 4, 2003
Accepted May 22, 2003
Immunomodulatory drug (Revamid) co-stimulates 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*
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard University, Boston VA Healthcare System, Boston, MA, USA
* Corresponding author; email: Nikhil_Munshi{at}dfci.harvard.edu.
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 more potent analogue of Thal, immunomodulatory drug (IMiD), on T-cells. Although IMiD3 (Revimid) does not directly stimulate proliferation of normal donor CD3+ T cells, it significantly co-stimulates proliferation of CD3+ T-cells induced by CD3 ligation (SI 2.4), immature DCs (SI 2.1), and mature DCs (SI 2.6). T cell proliferation triggered by DCs was abrogated by CTLA-4-Ig, and IMiD3 partially overcomes this inhibitory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4-Ig on EBV and Flu specific CD4 and CD8 T-cell responses, as measured by cytokine capture and ELISpot assay. IMiD3 did not induce upregulation 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 NF- B, a known downstream target of CD28 signaling. These results therefore define the co-stimulatory 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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