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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0804178v1 183/4/2837    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Hasan, A. N. Articles by O'Reilly, R. J. PubMed PubMed Citation Articles by Hasan, A. N. Articles by O'Reilly, R. J.

A Panel of Artificial APCs Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Dominant and Subdominant Viral Epitopes for Adoptive Therapy¹

Aisha N. Hasan^*, Wouter J. Kollen^*, Deepa Trivedi^*,, Annamalai Selvakumar, Bo Dupont, Michel Sadelain and Richard J. O'Reilly^2,*,,

^* Department of Pediatrics and Department of Immunology, The Marrow Transplantation Program, and Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Adoptive transfer of virus-specific T cells can treat infections complicating allogeneic hematopoietic cell transplants. However, autologous APCs are often limited in supply. In this study, we describe a panel of artificial APCs (AAPCs) consisting of murine 3T3 cells transduced to express human B7.1, ICAM-1, and LFA-3 that each stably express one of a series of six common HLA class I alleles. In comparative analyses, T cells sensitized with AAPCs expressing a shared HLA allele or autologous APCs loaded with a pool of 15-mer spanning the sequence of CMVpp65 produced similar yields of HLA-restricted CMVpp65-specific T cells; significantly higher yields could be achieved by sensitization with AAPCs transduced to express the CMVpp65 protein. T cells generated were CD8⁺, IFN-⁺, and exhibited HLA-restricted CMVpp65-specific cytotoxicity. T cells sensitized with either peptide-loaded or transduced AAPCs recognized epitopes presented by each HLA allele known to be immunogenic in humans. Sensitization with AAPCs also permitted expansion of IFN-⁺ cytotoxic effector cells against subdominant epitopes that were either absent or in low frequencies in T cells sensitized with autologous APCs. This replenishable panel of AAPCs can be used for immediate sensitization and expansion of virus-specific T cells of desired HLA restriction for adoptive immunotherapy. It may be of particular value for recipients of transplants from HLA-disparate donors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported through National Institutes of Health Grants CA23766 and CA59350, the Burton Abrams Charitable Trust, the Ryan E. McGeough Charitable Fund, the Aubrey Fund for Pediatric Cancer Research, The Larry H. Smead Foundation, the Commonwealth Foundation for Cancer Research, The Dutch Cancer Society, and The Claire L. Tow Chair in Pediatric Oncology Research.

² Address correspondence and reprint requests to Dr. Richard J. O'Reilly, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room H1409, New York, NY 10021. E-mail address: oreillyr{at}mskcc.org

³ Abbreviations used in this paper: HSCT, hematopoietic stem cell transplant; AAPC, artificial APC; CAM, cytokine-activated monocyte; AAPC^{class I}, single HLA class I-bearing AAPC; AAPC^{class I-pp65}, above AAPC transduced to express CMVpp65; PL AAPC^{class I}, PL CAMs, PL EBV-BLCL, CMVpp65 peptide pool-loaded AAPC or autologous CAM or EBV-BLCL; DCS, deficient calf serum; TC, T cell.

⁴ The online version of this article contains supplemental material.