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J Clin Invest. 1996 June 1; 97(11): 2642–2650.
PMCID: PMC507352

T cell receptor biases and clonal proliferations among lung transplant recipients with obliterative bronchiolitis.


Obliterative bronchiolitis (OB) is the most serious late complication of lung transplantation, but the pathogenesis of this disorder has not been elucidated. We sought evidence that OB is mediated by a cellular immunologic response by characterizing T cell antigen receptor beta-chain variable gene (TCRBV) repertoires in lung allograft recipients. Expression levels of 27 TCRBV among recipients were determined by multiprobe RNase protection assay after PCR amplification. In comparison to recipients with no evidence of rejection (n = 9), the PBL TCRBV repertoires of OB subjects (n = 16) exhibited more frequent expansions (16 vs. 9% of all measured TCRBV, P < 0.02), and the magnitudes of these abnormalities were greater (8.2 +/- 0.8 vs. 4.5 +/- 0.3 SD from mean normal values, P < 0.01). TCRBV sequencing showed these expansions were composed of clonal or oligoclonal populations. Thus, T cell responses in the recipients are marked by highly selective clonal expansions, presumably driven by indirect recognition of a limited number of immunodominant alloantigens. These processes are exaggerated among allograft recipients with OB, implying that cognate immune mechanisms are important in the pathogenesis of the disorder. Furthermore, the prominence of finite, distinct TCR phenotypes raise possibilities for development of novel diagnostic modalities and targeted immunotherapies for OB and other manifestations of chronic allograft rejection.

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Selected References

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  • Duncan SR, Paradis IL, Yousem SA, Similo SL, Grgurich WF, Williams PA, Dauber JH, Griffith BP. Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients. Am Rev Respir Dis. 1992 Dec;146(6):1419–1425. [PubMed]
  • Theodore J, Starnes VA, Lewiston NJ. Obliterative bronchiolitis. Clin Chest Med. 1990 Jun;11(2):309–321. [PubMed]
  • Azuma H, Tilney NL. Chronic graft rejection. Curr Opin Immunol. 1994 Oct;6(5):770–776. [PubMed]
  • Panzara MA, Oksenberg JR, Steinman L. The polymerase chain reaction for detection of T-cell antigen receptor expression. Curr Opin Immunol. 1992 Apr;4(2):205–210. [PubMed]
  • Theofilopoulos AN, Baccalà R, González-Quintial R, Kono DH, Balderas RS, Macphee R, Duncan SR, Roglic M. T-cell repertoires in health and disease. Ann N Y Acad Sci. 1995 Jul 7;756:53–65. [PubMed]
  • Krensky AM, Weiss A, Crabtree G, Davis MM, Parham P. T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med. 1990 Feb 22;322(8):510–517. [PubMed]
  • Colvin RB. Cellular and molecular mechanisms of allograft rejection. Annu Rev Med. 1990;41:361–375. [PubMed]
  • Adorini L, Guéry JC, Rodriguez-Tarduchy G, Trembleau S. Selective immunosuppression. Immunol Today. 1993 Jun;14(6):285–289. [PubMed]
  • Gaur A, Fathman CG. Immunotherapeutic strategies directed at the trimolecular complex. Adv Immunol. 1994;56:219–265. [PubMed]
  • Berry GJ, Brunt EM, Chamberlain D, Hruban RH, Sibley RK, Stewart S, Tazelaar HD. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990 Nov-Dec;9(6):593–601. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Plaza A, Kono DH, Theofilopoulos AN. New human V beta genes and polymorphic variants. J Immunol. 1991 Dec 15;147(12):4360–4365. [PubMed]
  • Kono DH, Baccala R, Balderas RS, Kovac SJ, Heald PW, Edelson RL, Theofilopoulos AN. Application of a multiprobe RNase protection assay and junctional sequences to define V beta gene diversity in Sezary syndrome. Am J Pathol. 1992 Apr;140(4):823–830. [PubMed]
  • Warrens AN, Lombardi G, Lechler RI. Presentation and recognition of major and minor histocompatibility antigens. Transpl Immunol. 1994 Jun;2(2):103–107. [PubMed]
  • Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol. 1977 Mar 1;29(1):1–5. [PubMed]
  • Miceli MC, Finn OJ. T cell receptor beta-chain selection in human allograft rejection. J Immunol. 1989 Jan 1;142(1):81–86. [PubMed]
  • Frisman DM, Hurwitz AA, Bennett WT, Boyle LA, Fallon JT, Dec GW, Colvin RB, Kurnick JT. Clonal analysis of graft-infiltrating lymphocytes from renal and cardiac biopsies. Dominant rearrangements of TcR beta genes and persistence of dominant rearrangements in serial biopsies. Hum Immunol. 1990 Jun;28(2):208–215. [PubMed]
  • Hand SL, Hall BL, Finn OJ. T-cell receptor gene usage and expression in renal allograft-derived T-cell lines. Hum Immunol. 1990 Jun;28(2):82–95. [PubMed]
  • Shirwan H, Chi D, Makowka L, Cramer DV. Lymphocytes infiltrating rat cardiac allografts express a limited repertoire of T cell receptor V beta genes. J Immunol. 1993 Nov 15;151(10):5228–5238. [PubMed]
  • Goss JA, Pyo R, Flye MW, Connolly JM, Hansen TH. Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells. J Exp Med. 1993 Jan 1;177(1):35–44. [PMC free article] [PubMed]
  • Krensky AM, Clayberger C. The induction of tolerance to alloantigens using HLA-based synthetic peptides. Curr Opin Immunol. 1994 Oct;6(5):791–796. [PubMed]
  • Shoskes DA, Wood KJ. Indirect presentation of MHC antigens in transplantation. Immunol Today. 1994 Jan;15(1):32–38. [PubMed]
  • Bradley JA, Mowat AM, Bolton EM. Processed MHC class I alloantigen as the stimulus for CD4+ T-cell dependent antibody-mediated graft rejection. Immunol Today. 1992 Nov;13(11):434–438. [PubMed]
  • Benichou G, Takizawa PA, Olson CA, McMillan M, Sercarz EE. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J Exp Med. 1992 Jan 1;175(1):305–308. [PMC free article] [PubMed]
  • Lee RS, Grusby MJ, Glimcher LH, Winn HJ, Auchincloss H., Jr Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo. J Exp Med. 1994 Mar 1;179(3):865–872. [PMC free article] [PubMed]
  • Fangmann J, Dalchau R, Fabre JW. Rejection of skin allografts by indirect allorecognition of donor class I major histocompatibility complex peptides. J Exp Med. 1992 Jun 1;175(6):1521–1529. [PMC free article] [PubMed]
  • Dalchau R, Fangmann J, Fabre JW. Allorecognition of isolated, denatured chains of class I and class II major histocompatibility complex molecules. Evidence for an important role for indirect allorecognition in transplantation. Eur J Immunol. 1992 Mar;22(3):669–677. [PubMed]
  • Liu Z, Sun YK, Xi YP, Maffei A, Reed E, Harris P, Suciu-Foca N. Contribution of direct and indirect recognition pathways to T cell alloreactivity. J Exp Med. 1993 Jun 1;177(6):1643–1650. [PMC free article] [PubMed]
  • Liu Z, Sun YK, Xi YP, Hong B, Harris PE, Reed EF, Suciu-Foca N. Limited usage of T cell receptor V beta genes by allopeptide-specific T cells. J Immunol. 1993 Apr 15;150(8 Pt 1):3180–3186. [PubMed]
  • Hedrick SM, Engel I, McElligott DL, Fink PJ, Hsu ML, Hansburg D, Matis LA. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. [PubMed]
  • McHeyzer-Williams MG, Davis MM. Antigen-specific development of primary and memory T cells in vivo. Science. 1995 Apr 7;268(5207):106–111. [PubMed]
  • Heber-Katz E, Acha-Orbea H. The V-region disease hypothesis: evidence from autoimmune encephalomyelitis. Immunol Today. 1989 May;10(5):164–169. [PubMed]
  • Burke CM, Theodore J, Dawkins KD, Yousem SA, Blank N, Billingham ME, Van Kessel A, Jamieson SW, Oyer PE, Baldwin JC, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest. 1984 Dec;86(6):824–829. [PubMed]
  • Argaet VP, Schmidt CW, Burrows SR, Silins SL, Kurilla MG, Doolan DL, Suhrbier A, Moss DJ, Kieff E, Sculley TB, et al. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus. J Exp Med. 1994 Dec 1;180(6):2335–2340. [PMC free article] [PubMed]
  • Morley JK, Batliwalla FM, Hingorani R, Gregersen PK. Oligoclonal CD8+ T cells are preferentially expanded in the CD57+ subset. J Immunol. 1995 Jun 1;154(11):6182–6190. [PubMed]
  • González-Quintial R, Baccalá R, Pope RM, Theofilopoulos AN. Identification of clonally expanded T cells in rheumatoid arthritis using a sequence enrichment nuclease assay. J Clin Invest. 1996 Mar 1;97(5):1335–1343. [PMC free article] [PubMed]

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