EXPRESSION OF CTLA4-Ig BY BIOLISTICALLY TRANSFECTED MOUSE ISLETS PROMOTES ISLET ALLOGRAFT SURVIVAL1

Gainer, Anita L.; Korbutt, Gregory S.; Rajotte, Ray V.; Warnock, Garth L.; Elliott, John F.

doi:10.1097/00007890-199704150-00019

Cited by 57 publications

(37 citation statements)

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“…Administration of a high dose of CTLA4-Ig was previously reported to suppress immune responses systemically [14,15,16,17], and several preceding studies indicate that local delivery of CTLA4-Ig prolongs the survival of islet allografts in mice [8,9,18]. Using adenovirus-mediated expression of CTLA4-Ig, investigators [26] recently reported that the production of CTLA4-Ig by islet cells themselves, but not by cells located in remote sites, is effective in prolonging islet allograft survival.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that the site-specific delivery of immunosuppressive molecules could provide an alternative strategy to avoid the hazardous side effects of conventional immunosuppressants [6,7,8,9]. Various immunosuppressive molecules have been tested in a variety of transplantation models and need to be assessed for their effectiveness on graft prolongation.…”

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confidence: 99%

“…A chimeric fusion protein, CTLA4-Ig, which is composed of the extracellular region of CTLA4 and the Fc portion of IgG1, similarly blocks the CD28-mediated co-stimulatory pathways, and down-regulates the immune response in various experimental transplantation models. When administered systemically [14,15,16,17] or expressed in engrafted tissues by gene transfer [8,9,18], CTLA4-Ig prolongs graft survival, and occasionally induces graft-specific unresponsiveness. However, it has not yet been established whether the prolongation of graft survival is obtained by a local or systemic immunoregulatory mechanism.…”

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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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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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“…A bimodal response has similarly been observed in other studies based on a local administration of CTLA4Ig. 14,15,33,34 The explanation for this response remains unclear. The expression level of CTLA4Ig may have to reach a threshold value in order to diffuse up to the regional lymph nodes and exert its immunomodulating effect.…”

Section: Figure 8 Photomicrographs Of Both Hind Limbs From a Dba/2j Mmentioning

confidence: 99%

“…13 The local delivery of CTLA4Ig was recently investigated in various cell transplantation protocols of islet allotransplantation: islets were either coated with CTLA4Ig before implantation 14 or genetically modified by biolistical transfection. 15 Co-transplantation of syngeneic C 2 C 12 myoblasts expressing CTLA4Ig together with allogeneic islets prolonged their survival under the mouse kidney capsule. 16 Adenoviral transduction of CTLA4Ig expression was reported to improve the survival of myeloid dendritic cells in allogeneic recipients significantly, 17 as well as pancreatic islets in xenogeneic recipients.…”

Section: Introductionmentioning

confidence: 99%

A self-immunomodulating myoblast cell line for erythropoietin delivery

2001

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Islet transplantation: present and future perspectives

Kenyon

Ranuncoli

Masetti

et al. 1998

Diabetes Metab. Rev.

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Islet cell transplantation can potentially normalize blood glucose levels and stop the progression of clinical complications, and if the transplant is done early in the course of the disease complications may be prevented. Remarkable progress has been made in recent years and islet cell transplantation has resulted in normalization of metabolic control in several patients with Type 1 diabetes in the absence of hypoglycemia. Only a few patients, however, have achieved insulin independence. Issues relating to islet cell engraftment within the liver, prevention of rejection and recurrent autoimmunity, and identification of alternative immunosuppressive drugs that do not adversely affect islet cell function remain to be solved. Thus far, the need for chronic, generalized immunosuppression to prevent rejection of the islets has limited the indication to those patients who have already received another transplant or to those who simultaneously receive islets and another organ (generally a kidney). Identification of immunointervention protocols that allow for engraftment in the absence of deleterious effects on the islets and prevent rejection and recurrent autoimmunity would make this procedure suitable for all patients, including children who have not yet developed long-term complications of the disease.

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EXPRESSION OF CTLA4-Ig BY BIOLISTICALLY TRANSFECTED MOUSE ISLETS PROMOTES ISLET ALLOGRAFT SURVIVAL1

Abstract: Transfection of allogeneic mouse islets with human CTLA4-Ig results in prolonged allograft survival. Although on histology mononuclear cells are present in the area of the transfected graft, they do not appear to infiltrate or destroy the islet graft.

Cited by 57 publications

References 10 publications

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

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

A self-immunomodulating myoblast cell line for erythropoietin delivery

Islet transplantation: present and future perspectives

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