Initial Depletion of Regulatory T Cells: the Missing Solution to Preserve the Immune Functions of T Lymphocytes Designed for Cell Therapy.
From: UMR CNRS 7087/UPMC, Hôpital Pitié Salpêtrière-Bâtiment CERVI, 83, Boulevard de l’Hôpital, 75013 Paris, France.
Blood
- Publish Date: Jan 2006
- ISSN: 0006-4971
- Volume: 107
- Issue: 1
- Pages: 381-8
- Medium: Print
- Language: English
- Citation (JAMA): Mesel-Lemoine Mariana, Cherai Mustapha, Le Gouvello Sabine, et al. Initial Depletion of Regulatory T Cells: the Missing Solution to Preserve the Immune Functions of T Lymphocytes Designed for Cell Therapy.. Blood Jan 2006;107:381-8
Abstract
We investigated the causes of the altered functionality of T cells cultured under conditions designed for cell and gene therapy and the strategies to prevent their defects. We first showed that human T cells cultured for 6 days with anti-CD3 +/- anti-CD28 antibodies and interleukin-2 presented a 50% decrease of their proliferative responses to allogeneic or recall antigens. Similarly, day-6 cultured murine T cells completely lost their capacity to reject allogeneic skin grafts and to provoke graft-versus-host disease (GVHD) when infused into irradiated semi-allogeneic mice. Interestingly, injection of higher amounts of cultured T cells restored GVHD induction. Moreover, depletion of CD25+ cells prior to T-cell cultures can prevent these deficiencies both in mice and humans. Therefore, we demonstrated that culture conditions used for T-cell therapy preferentially activated and expanded regulatory T cells (Treg’s). Thus, we showed that dividing cells sorted from T-cell cultures strongly suppressed the proliferation of autologous T cells in response to allogeneic stimulation. An increased detection of Foxp3 at mRNA and protein levels in the cultures confirmed the Treg expansion. Overall, we demonstrate that T-cell cultures promote Treg expansion over effector T cells, leading to deleterious immune functions, and that this imbalance can be prevented by an initial depletion of CD25+ cells.
Mesh Headings (Keywords): Animals, Antibodies, Monoclonal, Antigens, CD28, Antigens, CD3, Cell Culture Techniques, Cell Proliferation, Graft Rejection, Graft vs Host Disease, Humans, Immune Tolerance, Immunity, Cellular, Isoantigens, Lymphocyte Activation, Lymphocyte Depletion, Mice, T-Lymphocytes, T-Lymphocytes, Regulatory, Tissue Therapy
Check for Full Text / PubMed Unique Identifier (PMID): 16160005
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