Activated autologous T cells exert an anti-B-cell chronic lymphatic leukemia effect in vitro and in vivo.
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.
Di Ianni
Mauro
M
Department of Internal Medicine and Public Health, Chair of Hematology, University of L'Aquila, Italy. mauro.diianni@cc.univaq.it
Moretti
Lorenzo
L
Terenzi
Adelmo
A
Bazzucchi
Federico
F
Del Papa
Beatrice
B
Bazzucchi
Moira
M
Ciurnelli
Raffaella
R
Lucchesi
Alessandro
A
Sportoletti
Paolo
P
Rosati
Emanuela
E
Marconi
Pier Francesco
PF
Falzetti
Franca
F
Tabilio
Antonio
A
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
C508594:IL2 protein, human; D007155:Immunologic Factors; D007376:Interleukin-2; D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell