title: Activated autologous T cells exert an anti-B-cell chronic lymphatic leukemia effect in vitro and in vivo.
abstract: OBJECTIVE
  The impact of chronic lymphatic leukemia (CLL) tumor burden on the autologous immune system has already been demonstrated. This study attempted to elucidate the molecular mechanisms underlying T-cell immunologic deficiencies in CLL.
  
  
  METHODS
  Freshly isolated CD3(+) T cells from patients with a diagnosis of CLL and healthy donors were analyzed by gene expression profiling. Activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity against mutated and unmutated autologous B cells and DAUDI, K562 and P815 cell lines. To investigate T-cell mediated cytotoxicity in vivo, we co-transplanted OKT3-activated T lymphocytes and autologous B-cell CLL (B-CLL) cells into NOD/SCID mice.
  
  
  RESULTS
  Gene expression profiles of peripheral blood T cells from B-CLL patients showed 25 down-regulated, and 31 up-regulated, genes that were mainly involved in cell differentiation, proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T-cell activation. After culture, the T-cell count remained unchanged, CD8 cells expanded more than CD4 and a cytotoxicity index >30% was present in 5/20 patients. Cytotoxicity against B autologous leukemic cells did not correlate with B-cell mutational status. Only activated T cells exerting cytotoxicity against autologous leukemic B cells prevented CLL in a human-mouse chimera.
  
  
  CONCLUSIONS
  This study indicates that patients with CLL are affected by a partial immunologic defect that might be somewhat susceptible to repair. This study identifies the molecular pathways underlying T-cell deficiencies in CLL and shows that cytotoxic T-cell functions against autologous B-CLL can be rebuilt at least in part in vitro and in vivo.
authors.affiliation: Department of Internal Medicine and Public Health, Chair of Hematology, University of L'Aquila, Italy. mauro.diianni@cc.univaq.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretti
authors.forename: Adelmo
authors.initials: A
authors.lastname: Terenzi
authors.forename: Federico
authors.initials: F
authors.lastname: Bazzucchi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Del Papa
authors.forename: Moira
authors.initials: M
authors.lastname: Bazzucchi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ciurnelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lucchesi
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rosati
authors.forename: Pier Francesco
authors.initials: PF
authors.lastname: Marconi
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.forename: Antonio
authors.initials: A
authors.lastname: Tabilio
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D016853:Muromonab-CD3 / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: C508594:IL2 protein, human; D007155:Immunologic Factors; D007376:Interleukin-2; D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell