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• W2102905192 abstract "Cutting edge: identification of hepatitis C virus-specific CD8+T cells restricted by donor HLA alleles following liver transplantation. Rosen HR, Hinrichs DJ, Leistikow RL, Callender G, Wertheimer AM, Nishimura MI, Lewinsohn DM.By necessity, human liver transplantation is performed across HLA barriers. As a result, intracellular infection of the allograft presents a unique immunologic challenge for the recipient's immune system. In this study, we describe the presence of HLA-A2-restricted, hepatitis C virus (HCV)-specific CD8+T cells in liver transplant recipients in whom the allograft is HLA-A2 positive and the recipient is HLA-A2 negative. These memory-effector T cells are recipient derived and recognize HCV peptide uniquely in the context of HLA-A2. Furthermore, these cells were absent before the transplant, suggesting that the allograft is capable of selectively expanding naive CD8+T cells. The in vitro specificity to donor HLA allele-restricted CD8+T cells suggests that these cells may function to control HCV spread in the allograft.[Abstract reproduced by permission of J Immunol 2004;173:5355–5359] Cutting edge: identification of hepatitis C virus-specific CD8+T cells restricted by donor HLA alleles following liver transplantation. Rosen HR, Hinrichs DJ, Leistikow RL, Callender G, Wertheimer AM, Nishimura MI, Lewinsohn DM. By necessity, human liver transplantation is performed across HLA barriers. As a result, intracellular infection of the allograft presents a unique immunologic challenge for the recipient's immune system. In this study, we describe the presence of HLA-A2-restricted, hepatitis C virus (HCV)-specific CD8+T cells in liver transplant recipients in whom the allograft is HLA-A2 positive and the recipient is HLA-A2 negative. These memory-effector T cells are recipient derived and recognize HCV peptide uniquely in the context of HLA-A2. Furthermore, these cells were absent before the transplant, suggesting that the allograft is capable of selectively expanding naive CD8+T cells. The in vitro specificity to donor HLA allele-restricted CD8+T cells suggests that these cells may function to control HCV spread in the allograft. [Abstract reproduced by permission of J Immunol 2004;173:5355–5359] The receptor of virus-specific CD8+T lymphocytes (CTL) binds to the molecular complex of an 8–12 amino acid viral peptide bound to an autologous HLA class I molecule. Efficient triggering of T cell receptors leads to activation, cytokine secretion, and/or cytotoxicity. To ensure that a broad spectrum of T cells is able to respond to foreign antigens and to avoid at the same time autoreactivity, T cells are selected in the thymus according to their interaction with autologous HLA molecules and self-peptides: T cell precursors binding with high affinity to autologous HLA–peptide-complexes as well as those that cannot interact at all are deleted; on the other hand, T cells carrying T cell receptors that interact weakly with autologous HLA molecules—without T cell activation—are positively selected. This process leads to a population of circulating T cells which may be able to interact with high affinity with complexes of a foreign peptide bound to an autologous HLA molecule [[1]von Boehmer H. Aifantis I. Gounari F. Haughn L. Apostolou I. Jaeckel E. et al.Thymic selection revisited: how essential is it?.Immunol Rev. 2003; 191: 62-78Crossref PubMed Scopus (168) Google Scholar]. While this strategy has evolved over millions of years in mammals, allogeneic transplantation has been introduced rather recently, but creates a completely new challenge to the immune system. In the case of orthotopic liver transplantation (OLT), HLA matching of donor and recipient is not performed and the recipient's T cell repertoire is confronted with a whole set of new, i.e. foreign HLA molecules. Although T cell alloreactivity is still incompletely understood, it is likely that alloreactive T cells bind avidly to the foreign HLA molecule complexed with a self peptide, due either to a dominant interaction with the foreign HLA molecule, more or less ignoring the bound peptide, or due to interaction with the entire HLA-peptide complex, because the self-peptide is presented in a sterically different manner within the binding groove of the other HLA molecule [[2]Housset D. Malissen B. What dor TCR-pMHC crystal structures teach us about MHC restriction and alloreactivity?.Trends Immunol. 2003; 24: 429-437Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar]. The multitude of new HLA-peptide complexes present on donor cells may explain the high precursor frequency of alloreactive T cells which has been estimated to as high as 1:100. The situation for the immune system becomes even more demanding when the transplanted liver is infected by HCV. So far it has been unclear, whether recipient CTL would be able to recognize viral peptides on donor hepatocytes. The fact that some patients spontaneously clear HCV following initial reinfection of the graft [3Neumann U.P. Neuhaus P. Discussion on spontaneous resolution of chronic hepatitis C virus after withdrawal of immunosuppression.Gastroenterology. 2004; 126: 627Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 4Schirren C.A. Jung M-C. Worzfeld T. Mamin M. Baretton G. Gerlach J.T. et al.Hepatitis C virus-specific CD4+T cell response after liver transplantation occurs early, is multispecific, compartmentalizes to the liver, and does not correlate with recurrent disease.J Infect Dis. 2001; 183: 1187-1194Crossref PubMed Scopus (37) Google Scholar] and that about 20–25% of treatable patients respond to interferon/ribavirin therapy [[5]Bizollon T. Ahmed S.N. Radenne S. Chevallier M. Chevallier P. Parvaz P. et al.Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon–ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence.Gut. 2003; 52: 283-287Crossref PubMed Scopus (156) Google Scholar] suggested that the HCV-specific immune response can be effective even in the presence of immunosuppressive drugs. This was attributed to partial matches at the HLA class I locus or cross-reactivity between closely related HLA class I molecules. In addition, cytokine secretion by HCV-specific CD4+T cells could be a contributing factor, because recipient HLA class II positive antigen-presenting cells migrate into the graft and to a large extend replace the corresponding donor cells, permitting presentation of viral peptides to HCV-specific CD4+T cells by autologous HLA class II molecules [[6]Bittmann I. Bottino A. Baretton G. Gerbes A.L. Zachoval R. Rau H.G. et al.The role of graft-resident Kupffer cells and lymphocytes of donor type during the time course after liver transplantation—a clinico-pathological study.Virchows Arch. 2003; 443: 541-548Crossref PubMed Scopus (14) Google Scholar]. In fact, strong HCV-specific CD4+T cell responses have been shown to correlate with a better clinical course and response to antiviral therapy in HCV reinfection [7Weston S.J. Leistikow R.L. Reddy K.R. Torres M. Wertheimer A.M. Lewinsohn D.M. et al.Reconstitution of hepatitis C virus-specific T-cellmediated immunity after liver transplantation.Hepatology. 2005; 41: 72-81Crossref PubMed Scopus (61) Google Scholar, 8Schirren C.A. Zachoval R. Gerlach J.T. Ulsenheimer A. Gruener N.H. Diepolder H.M. et al.Antiviral treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation: association of a strong, multispecific, and long-lasting CD4+T cell response with HCV-elimination.J Hepatol. 2003; 39: 397-404Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Now, Rosen et al. add a fascinating new observation to that scenario by showing for the first time that priming of recipient CTL against HCV epitopes presented by donor HLA class I molecules occurs [[9]Rosen H.R. Hinrichs D.J. Leistikow R.L. Callender G. Wertheimer A.M. Nishimura M.I. et al.Cutting edge: identification of hepatitis C virus-specific CD8+T cells restricted by donor HLA alleles following liver transplantation.J Immunol. 2004; 173: 5355-5359PubMed Google Scholar]. In two out of five HCV infected patients who are HLA-A2 negative, but received a liver graft from an HLA-A2 positive donor, HLA-A2 restricted, HCV-specific CD8+T cells were demonstrated by HLA class I tetramer staining and further characterized in detail following T cell cloning. They could clearly show that the CTL were of recipient origin, were not present before OLT, and would not recognize the viral peptide in the context of autologous, recipient HLA class I molecules, suggesting de novo priming after reinfection of the graft, possibly by liver-resident, donor derived dendritic cells. Further studies now have to clarify the relative contribution of these HCV-specific, allo-restricted CTL to the overall HCV-specific CTL response and whether they are associated with viral control or hepatocellular injury, since Rosen et al. found these cells only 20 months and 4 years after OLT, respectively, whereas HCV reinfection and recurrent hepatitis C occur within weeks of transplantation and in many patients the subsequent course of HCV reinfection seems to be determined within the first few months after OLT. Another disturbing point is that from the point of view of the immune system, allo-restricted recognition of viral epitopes should not be different from allospecific immune responses leading to graft rejection. In this context HCV specific CD4+T cells may play a key role by augmenting virus-specific CD8+T cell responses over pure allospecific immune responses. Despite these open questions, there is the clear message from these data that to understand HCV-specific immune responses after OLT, CD8+ and perhaps also CD4+T cell responses restricted by donor HLA alleles have to be included in the analysis. It also further supports the common clinical practice to early reduce immunosuppression in HCV reinfected patients, since a subset of allogeneic immune responses may contribute to HCV control." @default.
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• W2102905192 title "CTL in HCV reinfection after OLT: Allospecific or virus-specific or both?" @default.
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• W2102905192 doi "https://doi.org/10.1016/j.jhep.2005.05.015" @default.
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