PREVENTION OF CHRONIC REJECTION IN MOUSE AORTIC ALLOGRAFTS BY COMBINED TREATMENT WITH CTLA4-Ig AND ANTI-CD40 LIGAND MONOCLONAL ANTIBODY1,2

Sun, Hong; Субботин, Владимир; Chen, Christopher; Aı̈touche, Abdelouahab; Valdivia, Luis A.; Sayegh, M. H.; Linsley, Peter S.; Fung, John J.; Starzl, Thomas E.; Rao, Abdul S.

doi:10.1097/00007890-199712270-00035

Cited by 91 publications

(46 citation statements)

References 13 publications

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“…The findings of this study are in apparent conflict with several reports that have suggested that CB or CB with donor cells can prevent chronic rejection (5,6,(31)(32)(33). For example, we have previously reported that simultaneous blockade of CD28 and CD40 pathways inhibits the chronic transplant vasculopathy in BALB/c heart grafts in C3H recipients (5), and other groups have demonstrated that blockade of these pathways inhibits transplant vasculopathy in C57BL/10 aortic grafts in C3H recipients (31), rat kidney (32), and heart allograft (33).…”

Section: Dst (contrasting

confidence: 99%

Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Shirasugi

Adams

Durham

et al. 2002

The Journal of Immunology

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We have previously described a nonirradiation-based regimen combining costimulation blockade, busulfan, and donor bone marrow cells that promotes stable, high level chimerism, deletion of donor-reactive T cells, and indefinite survival of skin allografts in mice. The purpose of the current study is to determine the efficacy of this tolerance regimen in preventing acute and chronic rejection in a vascularized heart graft model and to compare this regimen with other putative tolerance protocols. Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination with donor cells enjoyed markedly prolonged heart graft survival and initially preserved histological structure. However, tolerance was not achieved, as evidenced by the eventual onset of chronic rejection characterized by obliterative vasculopathy and the rejection of secondary skin grafts. In contrast, following treatment with costimulation blockade, busulfan, and bone marrow, heart grafts survived indefinitely without detectable signs of chronic rejection or structural damage, even 100 days after placement of a secondary donor skin graft. We detected multilineage chimerism in peripheral blood, spleen, lymph nodes, and thymus, and peripheral deletion of donor-reactive cells was complete by day 90. These findings indicate that only the CD40/CD28 blockade chimerism induction regimen prevents both acute and chronic rejection of vascularized organ transplants. Further testing of these strategies in a preclinical large animal model is warranted.

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Section: Dst (contrasting

confidence: 99%

Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Shirasugi

Adams

Durham

et al. 2002

The Journal of Immunology

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“…The treatment regimen has been different in the various studies, ranging from once at the time of transplantation until continuous administration every 72 hours to prevent chronic rejection in aortic allografts (147). In the latter case, also CD40L effector functions operating within the transplanted graft might be of importance (see 3.4.4).…”

Section: Cd40-cd40l: Role In Transplantationmentioning

confidence: 99%

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Kooten¹

2000

Front Biosci

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“…However an absolute requirement for CD28 costimulation for CD154 expression has not been universally reported (39,44). In addition, allograft recipients treated concurrently with CD40-CD154 and CD28-B7 blockade have a greater prolongation of survival than recipients' administration of either agent alone (4,(45)(46)(47). It is therefore likely that CD154 and B7 molecule expression are regulated by independent factors, but there is a degree of interdependence between the two costimulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

Bartlett¹,

McCall²,

Ameratunga³

et al. 2003

American Journal of Transplantation

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CD40-CD154 and/or CD28-CD80/86 costimulatory blockade induces long-term allograft survival in numerous animal models. Studies examining the expression of costimulatory molecules during acute cellular rejection (ACR) have been limited to renal and cardiac allografts.The aim of this study was to describe the relationship between intragraft costimulatory molecule expression in OLT recipients and ACR. Forty-five liver biopsies were obtained at reperfusion and day 7. Gene and protein expression of CD80, CD86 and CD154 were analyzed by RT-PCR and immunohistochemistry. CD154 protein expression was present in 13 of 18 patients with a RAI score of 4, but in only two of 14 patients with a RAI score of <4. There was a strong association between the RAI score and the presence of CD80 and CD154 immunoreactivity. CD86 protein expression did not correlate with the severity of ACR. In reperfusion biopsies CD154, but not CD80 or CD86, protein expression correlated with the total ischaemic time. There was no association between expression of costimulatory molecule genes and ACR.In conclusion, we have demonstrated an association between CD154 and CD80 protein expression and ACR in orthotopic liver allografts.

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PREVENTION OF CHRONIC REJECTION IN MOUSE AORTIC ALLOGRAFTS BY COMBINED TREATMENT WITH CTLA4-Ig AND ANTI-CD40 LIGAND MONOCLONAL ANTIBODY1,2

Abstract: Background-In this study, using a murine model of aortic allotransplantation, the role of blockade of signaling through CD28/B7 and CD40/CD40 ligand co-stimulatory pathways in the evolvement of posttransplant vasculopathy was examined.

Cited by 91 publications

References 13 publications

Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

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