Recently, we have shown that anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity against the host are endowed with marked veto activity and can facilitate bone marrow (BM) allografting without graft-versus-host disease. We also demonstrated synergism between rapamycin (RAPA) and the veto cells. CD4(+)CD25(+) T-regulatory (Treg) cells are suppressor cells that can enhance alloengraftment. We investigated whether donor Tregs would be synergistic with veto CTLs and RAPA in augmenting alloengraftment or, conversely, would suppress veto CTL effects. Lethally irradiated C3H mice were transplanted at day 2 after irradiation with Balb-nude BM. Graft rejection was induced by purified host-type T cells infused 1 day prior to BMT. The addition of Tregs led to moderate enhancement of engraftment. RAPA at different doses was synergistic with Tregs. The addition of veto CTLs to Tregs enabled reducing the effective RAPA dose fourfold. Combining all three agents was necessary to overcome rejection at low-dose RAPA. Chimerism analysis at 5 to 9 months revealed a significant presence of host-type cells coexisting with the predominant donor T cells, suggesting that tolerance had been attained. The synergistic effects between Tregs, veto CTLs, and RAPA offer an attractive approach for facilitating alloengraftment.

15 Jan 2006·TransplantationQ2 · MEDICINE

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

Q2 · MEDICINE

Article

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

BACKGROUNDCD8 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.METHODSCD8 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.RESULTSBALB/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.CONCLUSIONThese 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.

15 Dec 2004·TransplantationQ2 · MEDICINE

Effect of Mediators of Innate Immunity and Inflammation on CD8+ Veto Cells

Q2 · MEDICINE

Article

Author: Roback, John D. ; Zimring, James C. ; Hillyer, Christopher D. ; Chadwick, Traci E.

BACKGROUNDMethods of allotolerance induction that are successful in mice often fail in primates. Activators of innate immunity derived from microbial pathogens, which are present in primate populations but not in pathogen-free mouse colonies, have been shown to overcome tolerance induction by co-stimulatory blockade or regulatory T cells. Unlike other strategies, veto cells promote long-term allograft survival in primates. Accordingly, the authors hypothesized that veto cells are resistant to the effects of innate immune activation.METHODSUsing mixed lymphocyte reactions as a model of alloimmunization, the authors assessed the effect of inflammatory mediators on veto cell activity. RESULTS.: The authors demonstrate that the activity of veto cells is unaltered by lipopolysaccharide, double-stranded RNA, or interferon-gamma. Tumor necrosis factor-alpha modestly inhibited the veto effect, but only when veto cells were limiting.CONCLUSIONSThese findings may help to explain why veto cell-based therapies are more effective than other approaches in primate populations.

100 Deals associated with Anti-viral veto cell (Cell Source)

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Indication	Highest Phase	Country/Location	Organization	Date
Virus Diseases	Preclinical	US	Cell Source, Inc.	01 Sep 2019
Graft vs Host Disease	Preclinical	US	Cell Source, Inc.	29 Jul 2019
Anemia, Sickle Cell	Preclinical	IL	Cell Source, Inc.	-
Graft Rejection	Preclinical	IL	Cell Source, Inc.	-

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