Functional impairment of human T-lymphocytes following PHA-induced expansion and retroviral transduction: implications for gene therapy

Abstract

The immune function of retrovirus-mediated gene modified (GM) T cells is critical for

Inmunodeficiencia común variable: caracterización clínica e inmunológica de pacientes y definición de subgrupos homogéneos con base en la tipificación de subpoblaciones de linfocitos B

“…Esta diferencia en la proliferación de linfocitos T como reacción a la fitohemaglutinina y a los antígenos específicos, puede ser el resultado del aumento preferencial de linfocitos T de memoria central y la disminución de linfocitos T efectores causada por la fitohemaglutinina (49). Por lo tanto, es posible que la de ciertas células, citocinas y accesibilidad de los linfocitos T de memoria al antígeno, entre otras).…”

Functional and phenotypic variations in human T cells subjected to retroviral-mediated gene transfer

“…31 On the basis of this observation, and given that an impaired functionality of T cells has been previously related to the stimulation of T-cell samples, 18 we have now investigated whether by lowering the concentration of anti-CD3i during T-cell stimulation we could preserve both the susceptibility of the cells to retroviral transduction and also their cytolytic response to an allogeneic stimulus. The experiments shown in Figure 3 demonstrate that lowering the dose of anti-CD3i from the standard 1 mg/ml concentration to up to 0.1 ng/ml did not significantly modify the transduction of human T cells (P40.5 between all the paired samples studied).…”

“…A comparable functionality of Retroviral-mediated human T-cell transduction ML Lamana et al fresh and CD8 þ cells activated with anti-CD28i plus 0.5 mg/ml of anti-CD3i has been recently reported. 18 The re-stimulation of T cells after transduction that is employed in our protocol could explain this discrepancy due to a possible decrease in the response of CD8 þ cells after a new stimulus.…”

“…In addition, a number of studies have shown that PHA-activated lymphocytes display an impaired response to allogeneic stimulation. 18 Also impaired antiviral-specific responses have been described for T lymphocytes activated with anti-CD3. 19 In some instances, the addition of anti-CD28 partially prevented the repertoire skewing of T-cell populations, as well as the activation-induced death of these cells.…”

Control of graft-versus-host disease with maintenance of the graft-versus-leukemia effect in a murine allogeneic transplant model using retrovirally transduced murine suicidal lymphocytes

“…This strategy has been used in the clinic, and several small trials have provided proof of this concept, with results showing reduced GVHD after the administration of ganciclovir [5,13] in the setting of either donor lymphocyte infusion [5,[14][15][16][17] or T-cell add-back to T-cell-depleted marrow at the time of the initial transplantation [13]. However, lower than expected rates of GVHD and GVL were observed in these trials, suggesting that the ex vivo manipulations required to produce the T cells diminished their alloreactivity, possibly because of alterations in the composition of the lymphocyte subsets [10], prolonged culture duration and antibiotic selection [18][19][20][21], or the detrimental effects of exposure to high-dose interleukin (IL)-2 [7,18,22]. Nevertheless, the use of suicidal lymphocytes remains a promising strategy, and investigators in both the United States and Europe [23] have second-generation clinical trials already accruing patients or near to opening.…”