Delving into the Latest Updates on VETO Kidney Transplant with Synapse

Overview

Basic Info

Drug Type

Stem cell therapy

Synonyms-

Target-

Mechanism-

Therapeutic Areas

Immune System Diseases

Active Indication-

Inactive Indication

Renal transplant rejection

Originator Organization

Cell Source, Inc.

Active Organization-

Inactive Organization

Cell Source, Inc.

Drug Highest PhasePendingEarly Phase 1

First Approval Date-

Regulation-

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The liver has a role in T cell tolerance induction, which is mainly achieved through the functions of tolerogenic hepatic antigen-presenting cells (APCs) and regulatory T cells. Hepatic stellate cells (HSCs) are known to have various immune functions, which range from immunogenic antigen presentation to the induction of T cell apoptosis. Here we report a novel role for stellate cells in vetoing the priming of naive CD8 T cells. Murine and human HSCs and stromal cells (but not hepatocytes) prevented the activation of naive T cells by dendritic cells, artificial APCs, and phorbol 12-myristate 13-acetate/ionomycin by a cell contact–dependent mechanism. The veto function for inhibiting T cell activation was directly correlated with the activation state of HSCs and was most pronounced in HSCs from fibrotic livers. Mechanistically, high expression levels of CD54 simultaneously restricted the expression of interleukin-2 (IL-2) receptor and IL-2 in T cells, and this was responsible for the inhibitory effect because exogenous IL-2 overcame the HSC veto function. Conclusion: Our results demonstrate a novel function of HSCs in the local skewing of immune responses in the liver through the prevention of local stimulation of naive T cells. These results not only indicate a beneficial role in hepatic fibrosis, for which increased CD54 expression on HSCs could attenuate further T cell activation, but also identify IL-2 as a key cytokine in mediating local T cell immunity to overcome hepatic tolerance. (HEPATOLOGY 2011;)

27 Mar 2010·TransplantationQ2 · MEDICINE

Induction of B-Cell Immune Tolerance by Antigen-Modified Cytotoxic T Lymphocytes

Q2 · MEDICINE

Article

Author: Geiger, Terrence L. ; Nguyen, Phuong

BACKGROUND:

Third-party-specific cytotoxic T lymphocytes (CTL), or veto CTL, are being assessed as a cellular therapeutic for the induction of T-cell tolerance during transplantation. Conceptually, veto cell-expressed antigens (Ags) may induce B-cell immune responses, and this may have deleterious consequences. Whether veto cells induce immunity, tolerance, or are ignored by B lymphocytes has, however, not been addressed.

METHODS:

CTL were retrovirally transduced with a model cell surface Ag to generate veto CTL. The impact of CTL-specific Ag expression on the activation and tolerization of Ag-specific B cells was assessed in vitro and, using adoptive transfer models, in vivo.

RESULTS:

In vitro, CTL-expressed Ag induced an abortive proliferative response in specific B lymphocytes, whereby an initial proliferative burst was followed by cell death. In vivo, the administration of veto CTL also induced B-cell tolerance. Specific immunoglobulin was not detected after subsequent immunization with a veto cell-expressed Ag. Modeling of this effect with Ag-specific B-cell receptor transgenic B lymphocytes demonstrated that Ag-specific B cells were eliminated by the veto CTL; the cell division was accompanied by the exhaustion and depletion of responding cells. Veto-induced B-cell tolerance could be wholly abrogated by treatment with the toll-like receptor ligand lipopolysaccharide, implying that this tolerance resulted from the absence of adequate supplemental signals during antigenic stimulation.

CONCLUSIONS:

Veto CTL are effective promoters of B-cell tolerance. Further assessment of their therapeutic potential in this regard is warranted.

15 Jan 2006·TransplantationQ2 · MEDICINE

Rapamycin Prolongs Susceptibility of Responding T Cells to Tolerance Induction by CD8+ Veto Cells

Q2 · MEDICINE

Article

Author: Anderson, Kimberly M. ; Zimring, James C.

BACKGROUND:

CD8 veto cells are an antigen-specific immunoregulatory cell type that induces tolerance by causing apoptosis in T cells that recognize antigens on the veto cell. However, responding T cells are only susceptible to veto based deletion for a 48-hour window, which represents a severe limitation to the use of veto cells as a cellular therapeutic. Several immunosuppresant drugs inhibit T cell differentiation at distinct points. We hypothesized that immunosuppresants, which arrest T cell differentiation, would maintain responding T cells in a vetoable state.

METHODS:

CD8 veto cells were generated from BALB/c (H-2) mice. The 2C transgenic mouse, which expresses a T cell receptor specific for L was used to visualize responding cells. Veto activity was measured by both visualizing apoptosis of the responding 2C T cells and by measuring a decrease in lysis of H-2 targets. Several immunosuppressant drugs were tested for their effect on veto cell activity.

RESULTS:

BALB/c veto cells exhibited a potent and antigen-specific deletion of 2C responder cells, but not mature 2C effectors. The addition of rapamycin significantly extended the window of opportunity to veto based deletion by preventing the responding 2C T cells from differentiating out of a vetoable state.

CONCLUSION:

These findings demonstrate that by utilizing rapamycin, the window of opportunity for veto-based induction of tolerance to transplantation antigens is significantly extended. This approach circumvents a serious obstacle in the development of veto cells as an efficacious cellular therapy to induce allospecific tolerance to transplantation antigens.

100 Deals associated with VETO Kidney Transplant

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