Mechanism of Anti-asialo GM1 Prevention of Graft-vs-Host Disease: Identification of Allo-antigen Activated T Cells

Charley, Michael R.; Mikhael, Anwar; Hackett, John; Kumar, Vinay; Bennett, Michael

doi:10.1111/1523-1747.ep12464858

Cited by 18 publications

(12 citation statements)

References 18 publications

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“…It remains controversial whether asialo GM1 expression represents a marker of CD8 + T-cell activation or identifies a distinct population of killer T cells with unique functional properties (32)(33)(34)(35)(36)(37). Our observations that asialo GM1 expression increases with the number of cell divisions (data not shown) and that anti-asialo GM1 can prevent CD8 expansion while sparing nondividing CD8 cells suggest that asialo GM1 is indeed an activation marker.…”

Section: Discussionmentioning

confidence: 99%

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Trambley¹,

Bingaman²,

Lin³

et al. 1999

J. Clin. Invest.

331

295

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Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1 + CD8 + cells play a critical role in this costimulation blockade-resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

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Section: Discussionmentioning

confidence: 99%

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Trambley¹,

Bingaman²,

Lin³

et al. 1999

J. Clin. Invest.

331

295

View full text Add to dashboard Cite

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“…The glycolipid ASGM-1 is expressed by NK cells, and the polyclonal anti-ASGM-1 has been reported to deplete NK activity specifically (14). ASGM-1 is also expressed, however, by dendritic cells, macrophages, and cytotoxic T cells (29,30). Treatment with anti-ASGM-1 in vivo can suppress NK function without affecting T cell immune reactions (31), although inhibition of cytotoxic T cells has been reported (32).…”

Section: Discussionmentioning

confidence: 99%

Tolerance, Mixed Chimerism, and Chronic Transplant Arteriopathy

Russell¹,

Chase²,

Sykes

et al. 2001

The Journal of Immunology

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Much evidence supports the conclusion that immunological responses to donor-specific incompatibilities are a major factor in producing “chronic” transplant rejection, including the arteriopathy (atherosclerosis) commonly present. Our experiments explored the effects of altered immunological responsiveness to these Ags on the formation of arteriopathy in transplanted mouse hearts. Specific immunological nonreactivity, or tolerance, was induced either by neonatal administration of allogeneic spleen cells (from F1 donors between class I-mismatched donor and recipient strains), resulting in “classical” immunological tolerance, or by bone marrow infusion to suitably prepared adult recipients, either fully MHC mismatched or class I mismatched, yielding “mixed chimerism.” Both approaches obviated systemic graft-versus-host effects. In both groups, donor-specific skin grafts survived perfectly and donor cell chimerism persisted. Specific Abs were undetectable in all recipients. Most transplants to either group of tolerant recipients developed striking vasculopathy in their coronary arteries (12 of 15 in neonatal tolerance and 15 of 23 in mixed chimeras). Neointimal infiltrates included CD4 and CD8 T cells and macrophages. Only 2 of 29 contemporary isotransplants showed any evidence of vasculopathy. Recipients essentially incapable of T and B cell responses (C.B-17/SCID and RAG1−/−) were also used. Transplants into these animals developed vasculopathy in 16 of 31 instances. Accordingly, in this setting, vasculopathy develops in the presence of H-2 gene-determined incompatibility even with minimal conventional immune reactivity. Perhaps innate responsiveness, that could include NK cell activity, can create such arteriopathic lesions. More evidence is being sought regarding this process.

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“…Previously, it was shown that this antibody could deplete mice of their NK cells, activated T cells and activated macrophages. 27,28 Since the NIH-bg-nu-xidBR mice lack NK and T cells, this antibody will deplete the activated macrophages. Even when 3.3 times more MG-2F11 cells (10 6 cells) were injected into these immunodeficient mice, none of the control mice developed a tumor, while four out of five mice pretreated with the anti-asialo GM1 antibody formed the MG-2F11 tumor (Fig 4c).…”

Section: Mm-csf-transfected U251mg Cells Did Not Grow In Subcutaneousmentioning

confidence: 99%

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

et al. 2003

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Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins Martin R Jadus, Human U251MG glioma cells retrovirally transduced with the human gene for the membrane form of macrophage colonystimulating factor (mM-CSF) were investigated. The clones, MG-2F11 and MG-2C4, that expressed the most mM-CSF, but not the viral vector or the parental U251MG cells, were killed by both murine and human monocyte/macrophages in cytotoxicity assays. MG-2F11 cells failed to form subcutaneous tumors in either nude or NIH-bg-nu-xidBR mice, while mice inoculated with the U251MG viral vector (MG-VV) cells developed tumors. Electron microscopy studies showed that 4 hours after subcutaneous injection, the mM-CSF-transduced cells began dying of a process that resembled paraptosis. The dying tumor cells were swollen and had extensive vacuolization of their mitochondria and endoplasm reticulum. This killing process was complete within 24 hours. Macrophage-like cells were immediately adjacent to the killed MG-2F11 cells. Immunohistological staining for the heat shock proteins HSP60, HSP70 and GRP94 (gp96) showed that 18 hours after inoculation into nude mice, the MG-2F11 injection site was two to four times more intensely stained than the MG-VV cells. This study shows that human gliomas transduced with mM-CSF have the potential to be used as a safe live tumor cell vaccine.

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Mechanism of Anti-asialo GM1 Prevention of Graft-vs-Host Disease: Identification of Allo-antigen Activated T Cells

Cited by 18 publications

References 18 publications

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Tolerance, Mixed Chimerism, and Chronic Transplant Arteriopathy

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

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