title: Rapid T cell repopulation after rabbit anti-thymocyte globulin (rATG) treatment is driven mainly by cytomegalovirus.
abstract: Rabbit anti-thymocyte globulin (rATG) induces a long-lasting lymphocytopenia. CD4(+)  T cells remain depleted for up to 2 years, whereas the CD8(+)  T cell compartment is refilled rapidly by highly differentiated CD27(-) CD45RA(+) CD57(+) effector-type cells. Because the presence of these highly differentiated CD8(+)  T cells has been associated with cytomegalovirus (CMV) infection, we questioned to what extent restoration of CMV T cell immunity contributes to the re-emergence of T cells following rATG treatment. We compared T cell repopulation in six CMV-seropositive patients with CMV reactivation (reactivating CMV(+) ) to that in three CMV(+)  patients without reactivation (non-reactivating CMV(+) ), and to that in three CMV-seronegative recipients receiving a kidney from a CMV-seronegative donor (CMV(-/-) ). All patients received rATG because of acute allograft rejection. Total CD4 and CD8 counts, frequency and phenotype of virus-specific CD8(+)  T cells were determined. In reactivating CMV(+)  patients, total CD8(+)  T cells reappeared rapidly, whereas in non-reactivating CMV(+)  patients they lagged behind. In CMV(-/-)  patients, CD8(+)  T cell counts had not yet reached pretransplant levels after 2 years. CMV reactivation was indeed followed by a progressive accumulation of CMV-specific CD8(+)  T cells. During lymphocytopenia following rATG treatment, serum interleukin (IL)-7 levels were elevated. Although this was most prominent in the CMV-seronegative patients, it did not result in an advantage in T cell repopulation in these patients. Repopulated CD8(+)  T cells showed increased skewing in their Vβ repertoire in both CMV(-/-)  and reactivating CMV-seropositive patients. We conclude that rapid T cell repopulation following rATG treatment is driven mainly by CMV.
authors.affiliation: Renal Transplant Unit, Department of Internal Medicine Department of Experimental Immunology, Academic Medical Center Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, Amsterdam, the Netherlands. s.h.havenith@amc.uva.nl
authors.forename: S H C
authors.initials: SH
authors.lastname: Havenith
authors.forename: E B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.forename: F J
authors.initials: FJ
authors.lastname: Bemelman
authors.forename: S L
authors.initials: SL
authors.lastname: Yong
authors.forename: K A M I
authors.initials: KA
authors.lastname: van Donselaar-van der Pant
authors.forename: R A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: I J M
authors.initials: IJ
authors.lastname: Ten Berge
mesh_terms: D000328:Adult; D000818:Animals; D000961:Antilymphocyte Serum / Q000276:immunology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D004279:DNA, Viral / Q000097:blood; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000627:therapeutic use; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000627:therapeutic use; D015851:Interleukin-7 / Q000097:blood; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000276:immunology* / Q000821:virology; D011817:Rabbits; D000077562:Valganciclovir; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D014775:Virus Activation; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D004279:DNA, Viral; C508605:IL7 protein, human; D007166:Immunosuppressive Agents; D015851:Interleukin-7; D000077562:Valganciclovir; D015774:Ganciclovir