In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia

Mark Bonyhadi, Mark Frohlich, Angela Rasmussen, Christophe Ferrand, Laura Grosmaire, Eric Robinet, Jose Leis, Richard Maziarz, Pierre Tiberghien, Ronald J. Berenson

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2366-2375
Number of pages10
JournalJournal of Immunology
Volume174
Issue number4
StatePublished - Feb 15 2005

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
T-Lymphocytes
B-Lymphocytes
In Vitro Techniques
CD40 Ligand
Therapeutic Uses
Granulocyte-Macrophage Colony-Stimulating Factor
Up-Regulation
Cell Culture Techniques
Cell Count
Clinical Trials

ASJC Scopus subject areas

  • Immunology

Cite this

Bonyhadi, M., Frohlich, M., Rasmussen, A., Ferrand, C., Grosmaire, L., Robinet, E., ... Berenson, R. J. (2005). In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia. Journal of Immunology, 174(4), 2366-2375.

In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia. / Bonyhadi, Mark; Frohlich, Mark; Rasmussen, Angela; Ferrand, Christophe; Grosmaire, Laura; Robinet, Eric; Leis, Jose; Maziarz, Richard; Tiberghien, Pierre; Berenson, Ronald J.

In: Journal of Immunology, Vol. 174, No. 4, 15.02.2005, p. 2366-2375.

Research output: Contribution to journalArticle

Bonyhadi, M, Frohlich, M, Rasmussen, A, Ferrand, C, Grosmaire, L, Robinet, E, Leis, J, Maziarz, R, Tiberghien, P & Berenson, RJ 2005, 'In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia', Journal of Immunology, vol. 174, no. 4, pp. 2366-2375.
Bonyhadi M, Frohlich M, Rasmussen A, Ferrand C, Grosmaire L, Robinet E et al. In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia. Journal of Immunology. 2005 Feb 15;174(4):2366-2375.
Bonyhadi, Mark ; Frohlich, Mark ; Rasmussen, Angela ; Ferrand, Christophe ; Grosmaire, Laura ; Robinet, Eric ; Leis, Jose ; Maziarz, Richard ; Tiberghien, Pierre ; Berenson, Ronald J. / In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia. In: Journal of Immunology. 2005 ; Vol. 174, No. 4. pp. 2366-2375.
@article{e5f2a077c4f64dda9d137b8063d7b367,
title = "In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia",
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.",
author = "Mark Bonyhadi and Mark Frohlich and Angela Rasmussen and Christophe Ferrand and Laura Grosmaire and Eric Robinet and Jose Leis and Richard Maziarz and Pierre Tiberghien and Berenson, {Ronald J.}",
year = "2005",
month = "2",
day = "15",
language = "English (US)",
volume = "174",
pages = "2366--2375",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "4",

}

TY - JOUR

T1 - In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia

AU - Bonyhadi, Mark

AU - Frohlich, Mark

AU - Rasmussen, Angela

AU - Ferrand, Christophe

AU - Grosmaire, Laura

AU - Robinet, Eric

AU - Leis, Jose

AU - Maziarz, Richard

AU - Tiberghien, Pierre

AU - Berenson, Ronald J.

PY - 2005/2/15

Y1 - 2005/2/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=13544256621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13544256621&partnerID=8YFLogxK

M3 - Article

VL - 174

SP - 2366

EP - 2375

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -