The role of CD40 in the regulation of humoral and cell-mediated immunity

Durie, Fiona H.; Foy, Teresa M.; Masters, Sally R.; Laman, Jon D.; Noelle, Randolph J.

doi:10.1016/0167-5699(94)90269-0

Cited by 344 publications

(183 citation statements)

References 47 publications

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“…Since the polyclonal B cell activators LPS and CD40L have been shown to alter the IL-4 responsiveness of B cells [6], [37], we analyzed IL-4 signaling in resting and activated B cells. After IL-4 treatment, a tyrosine phosphorylated protein of 180 kDa (IRS2) was precipitated by anti-IRS2 and coprecipitated with antibodies to the p85 subunit of PI 3 kinase in both resting and activated splenic B cells (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation

et al. 2001

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IL-4 is an important B cell survival and growth factor. IL-4 induced the tyrosine phosphorylation of IRS2 in resting B lymphocytes and in LPS-or CD40L-activated blasts. Phosphorylated IRS2 coprecipitated with the p85 subunit of PI 3' kinase in both resting and activated cells. By contrast, association of phosphorylated IRS2 with GRB2 was not detected in resting B cells after IL-4 treatment although both proteins were expressed. However, IL-4 induced association of IRS2 with GRB2 in B cell blasts. The pattern of IL-4-induced recruitment of p85 and GRB2 to IRS2 observed in B cells derived from STAT6 null mice was identical to that observed for normal mice. While IL-4 alone does not induce activation of MEK, a MEK1 inhibitor suppressed the IL-4-induced proliferative response of LPS-activated B cell blasts. These results demonstrate that costimulation of splenic B cells alters IL-4-induced signal transduction independent of STAT6 leading to proliferation. Furthermore, proliferation induced by IL-4 in LPS-activated blasts is dependent upon the MAP kinase pathway.

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Section: Resultsmentioning

confidence: 99%

Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation

et al. 2001

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“…There are several possible reasons for the different responses of these mice. For instance, it is now evident that the co-stimulatory signals for T-cells are redundant and that several ligand and receptor pairs including the CD40/CD40 ligand pathway are involved in T-cell activation [29]. Therefore, blockage of the CD28-dependent co-stimulatory signals by CTLA4-Ig alone might not have been sufficient for the complete suppression of T cells.…”

mentioning

confidence: 99%

Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion

et al. 2002

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Aims/hypothesis. This study examined whether locally expressed CTLA4-Ig can suppress the accelerated islet allograft rejection that is induced by donor-specific transfusion.Methods. CTLA4-Ig-transfected or parental MIN6 cells were transplanted subcutaneously into the right flank of streptozotocin-induced diabetic C3H/Hej mice with or without donor-specific transfusion. For donor-specific transfusion, spleen cells from C57BL/6 mice were injected i.v. at the time of transplantation. In other experiments, CTLA4-Ig-transfected and parental MIN6 cells were transplanted separately into each flank, together with donor-specific transfusion. Rejection was defined as a blood glucose concentration of more than 300 mg/dl in two consecutive measurements, and graft survival was confirmed by hyperglycaemia after the grafts were removed. The effect of an anti-CTLA4 antibody on the survival of CTLA4-Ig-transfected MIN6 cells was also examined.Results. In 7 of 12 donor-specific transfusion sensitised mice, CTLA4-Ig-transfected MIN6 cells remained viable 20 days after grafting, whereas all parental MIN6 cells (n = 10) were rejected promptly, within 14 days. The prolonged allograft survival was observed even in the absence of detectable levels of serum CTLA4-Ig, while the surviving allografts continued to produce CTLA4-Ig in situ. This protection was abrogated by an anti-CTLA4 antibody, but not by a control antibody. Furthermore, six animals that maintained normoglycaemia after the separate transplantation of parental and CTLA4-Ig-transfected MIN6 cells into each flank all showed abrupt hyperglycaemia after the CTLA4-Ig/MIN6 graft was removed, suggesting that this protection operated locally. Conclusion/interpretation. A beta-cell line genetically engineered to secrete CTLA4-Ig can protect a graft locally from the alloimmune response induced by donorspecific transfusion. [Diabetologia (2002) The insulin-secreting islets comprise only a small fraction of the whole pancreas (~1%); therefore, the transplantation of purified islets rather than the whole pancreas seems to be a reasonable approach to control metabolic dysfunction in patients with Type I (insulindependent) diabetes mellitus. Although the survival of vascularised pancreas allografts at one year has significantly improved following the introduction of T cellspecific immunosuppressants such as cyclosporin and FK506 [1], the survival of pancreatic islet grafts under the same immunosuppressive regimen is still under 30% one year after transplantation [2]. However, a current study reports that seven consecutive patients attained sustained insulin independence after pancreatic islet transplantation [3]. All these recipients were

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“…19 In T cell-dependent B cell responses, binding of antigen to the TCR leads to the engagement of CD40L on T cells with CD40 on cognate B cells. 12 Ligation of CD40L with CD40 seems to activate a cascade of events involving the interaction of two receptors on the T cell, CD28 and CTLA4 with ligands, B7.1 and B7.2, on the B cell or APC. 12 Previous studies by Yang et al 20 successfully demonstrated the prevention of T cell activation to adenoviral vectors by administering CD40L antibody at the time of virus administration.…”

Section: Figure 5 Immunophenotyping Of the Liver Immunohistochemicalmentioning

confidence: 99%

“…12 Ligation of CD40L with CD40 seems to activate a cascade of events involving the interaction of two receptors on the T cell, CD28 and CTLA4 with ligands, B7.1 and B7.2, on the B cell or APC. 12 Previous studies by Yang et al 20 successfully demonstrated the prevention of T cell activation to adenoviral vectors by administering CD40L antibody at the time of virus administration. In addition, CD40L knockout mice showed persistence of transgene expression, as well as the ability to readminister virus when E1-deleted adenovirus was instilled into these animals.…”

Section: Figure 5 Immunophenotyping Of the Liver Immunohistochemicalmentioning

confidence: 99%

“…11 CD40 ligand (CD40L) is transiently up-regulated on the T cell subsequently binding to CD40 on APCs. 12 This signals the APC to increase B7 which binds to CD28 on the T cell, resulting in cytokine secretion and full T cell activation. 13 Blockade of either CD40L-CD40 or CD28-B7 interactions at the time of virus administration might suppress the activation of the immune response and lead to stable gene expression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig

1998

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The role of CD40 in the regulation of humoral and cell-mediated immunity

Cited by 344 publications

References 47 publications

Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation

Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation

Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion

Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig

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