In Vitro Engagement of CD3 and CD28 Corrects T Cell Defects in Chronic Lymphocytic Leukemia
- 15 February 2005
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 174 (4), 2366-2375
- https://doi.org/10.4049/jimmunol.174.4.2366
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells concomitant with immunological abnormalities and depressed immune responses. The T cell abnormalities found in CLL patients are thought to increase the risk of infection and hamper immune recognition and elimination of leukemic cells. We evaluated whether providing signals through CD3 and CD28 would correct some of these T cell defects. PBMC were incubated with anti-CD3 and anti-CD28 mAbs conjugated to superparamagnetic beads for 12–14 days. This resulted in a 1400-fold increase in T cell numbers. Activated T cells expressed high levels of CD25, CD54, CD137, and CD154, and produced IFN-γ, TNF-α, and GM-CSF. The mean T cell composition of cultures increased from ∼6% to >90% and leukemic B cells decreased from a mean of ∼85% to 0.1% or less. Leukemic B cells up-regulated expression of CD54, CD80, CD86, and CD95. Receptor up-regulation required direct cell contact with the activated T cells and could be blocked with anti-CD154 mAb, suggesting that the CD40-CD40L pathway helped mediate these effects. Poor T cell responses to allostimulation were corrected by the activation and expansion process. The skewing in the TCR repertoire returned to normal, or near normal following the culture process in eight of nine patients with abnormal TCR repertoires. Activated T cells had potent in vitro antileukemic effects in contrast to nonactivated T cells. Based upon these findings, a clinical trial has been initiated to test the potential therapeutic effects of T cells activated using this approach in patients with CLL.Keywords
This publication has 31 references indexed in Scilit:
- Immune reconstitution following autologous transfers of CD3/CD28 stimulated CD4+ T cells to HIV-infected personsClinical Immunology, 2004
- Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantationBlood, 2003
- Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemiaBlood, 2003
- Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor LymphocytesScience, 2002
- Retrovirus-Mediated Gene Transfer in Primary T Lymphocytes: Influence of the Transduction/Selection Process and ofex VivoExpansion on the T Cell Receptor β Chain Hypervariable Region RepertoireHuman Gene Therapy, 2000
- Role of the CD40 and CD95 (APO‐1/Fas) antigens in the apoptosis of human B‐cell malignanciesBritish Journal of Haematology, 1997
- Restrictions of T cell receptor beta chain repertoire in the peripheral blood of patients with systemic lupus erythematosus.Annals Of The Rheumatic Diseases, 1996
- Spread of clonal T-cell expansions in rheumatoid arthritis patientsHuman Immunology, 1996
- T-cell repertoire diversity and clonal expansions in normal and clinical samplesImmunology Today, 1995
- Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.The Journal of Experimental Medicine, 1993