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Oligoclonal CD4⁺ T Cell Expansions in Lung Transplant Recipients with Obliterative Bronchiolitis

Department of Immunology, Scripps Research Institute, La Jolla; Department of Medicine, Stanford University Medical Center, Stanford, California; and Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Steven R. Duncan, M.D., Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, 628 NW MUH, 3459 Fifth Ave., Pittsburgh, PA 15213. E-mail: duncsr{at}msx.upmc.edu

Obliterative bronchiolitis (OB) is a dreaded and frequent complication of lung transplantation with a poorly understood immunopathogenesis. To further evaluate disease mechanisms, we used T cell antigen receptor (TCR) ß-chain variable region RNase protection assays, after polymerase chain reaction amplification of TCR cDNA, to quantitate circulating CD4⁺ and CD8⁺ repertoires of transplant recipients with OB or no evidence of rejection (NER). All six recipients with OB had markedly abnormal CD4 expansions (2.5 ± 0.5 expansions/recipient) attributable to oligoclonal proliferations. Only two of six recipients with NER had a single, much lesser, CD4⁺ abnormality each (p < 0.01). Moreover, one of these patients developed OB shortly thereafter, and the other NER abnormality may have predated transplantation. In contrast, CD8⁺ expansions were common in both recipient populations. Findings of CD4⁺ expansions had 100% sensitivity and 80% specificity for the presence or imminent development of OB. These data suggest proliferations of CD4⁺ T cells are important in OB pathogenesis, and these are most likely part of a major histocompatibility complex Class II–dependent process of indirect alloantigen presentation. These CD4⁺ clones are likely to have facultative helper functions for the multiple and diverse immune processes that have been implicated in OB. Furthermore, the close association of CD4⁺ expansions with OB raises possibilities of development of novel diagnostic and therapeutic approaches.

Key Words: T lymphocytes • lung transplantation • graft rejection

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