Inhibition of Polymorphonuclear Leukocyte–Mediated Graft Damage Synergizes With Short-Term Costimulatory Blockade to Prevent Cardiac Allograft Rejection

El-Sawy, Tarek; Belperio, John A.; Strieter, Robert M.; Remick, Daniel G.; Fairchild, Robert L.

doi:10.1161/circulationaha.104.516708

Cited by 94 publications

(82 citation statements)

References 35 publications

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“…31 In parallel with the diminished infiltration of neutrophils, fewer CD4 ϩ and CD8 ϩ cells were observed on day 4 after transplant in allografts from IL-17 KO versus wild-type recipients ( Figure 3A). Quantitative realtime PCR and flow cytometry analyses confirmed that levels of CD3 and IFN␥ mRNA expression as well as total numbers of infiltrating CD4 ϩ and CD8 ϩ T cells were reduced in grafts from IL-17 KO recipients ( Figure 3B and C).…”

Section: T Cell Recruitment Into Cardiac Allografts Is Delayed In Il-mentioning

confidence: 82%

Interleukin-17 Promotes Early Allograft Inflammation

Gorbacheva

Fan

et al. 2010

The American Journal of Pathology

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Acute cellular rejection of organ transplants is executed by donor-reactive T cells, which are dominated by interferon-␥-producing cells. As interferon-␥ is dispensable for graft destruction, we evaluated the contribution of interleukin-17A (IL-17) to intragraft inflammation in major histocompatibility complex-mismatched heart transplants. A/J (H-2 a ) cardiac allografts placed into wild-type BALB/c (H-2 d ) mice induced intragraft IL-17 production on day 2 after transplant. Allografts placed into BALB/c IL-17 ؊/؊ recipients demonstrated diminished production of the chemokines CXCL1 and CXCL2 and delayed neutrophil and T cell recruitment. However, by day 7 after transplant, allografts from IL-17 ؊/؊ and wild-type recipients had comparable levels of cellular infiltration. The priming of donor-specific T cells was not affected by the absence of IL-17, and the kinetics of cardiac allograft rejection were similar in wild-type and IL-17 ؊/؊ recipients. In contrast, IL-17 ؊/؊ mice depleted of CD8 T cells rejected A/J allografts in a delayed fashion compared with CD8-depleted wild-type recipients. Although donorreactive CD4 T cells were efficiently activated in both groups, the infiltration of effector T cells into allografts was impaired in IL-17 ؊/؊ recipients. Our data indicate that locally produced IL-17 amplifies intragraft inflammation early after transplantation and promotes tissue injury by facilitating T cell recruitment into the graft. Targeting the IL-17 signaling network in conjunction with other graft-prolonging therapies may decrease this injury and improve the survival of transplanted organs.

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Section: T Cell Recruitment Into Cardiac Allografts Is Delayed In Il-mentioning

confidence: 82%

Interleukin-17 Promotes Early Allograft Inflammation

Gorbacheva

Fan

et al. 2010

The American Journal of Pathology

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“…Using a mouse model of fully mismatched heart transplantation, the Fairchild group (75) showed that treatment with Abs to the murine chemokine KC/ CXCL1, a known chemoattractant for PMNs, attenuated neutrophil infiltration of the allograft and prolonged its survival. More recently, these investigators showed that short-term costimulatory blockade combined with either peritransplant depletion of PMNs or treatment with Abs for KC/CXCL1 plus MIP-2/CXCL2 prolongs survival of fully mismatched cardiac allografts for Ͼ100 days (76). Although induced neutropenia is not clinically practical for organ transplantation, these studies suggest short-term, targeted interruption of neutrophil trafficking combined with other immune modulating agents may provide a more feasible approach.…”

Section: Cells Of the Innate Immune System As Participants In Allogramentioning

confidence: 99%

The Innate Immune System in Allograft Rejection and Tolerance

LaRosa

Rahman

Turka

2007

The Journal of Immunology

171

121

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As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a “rediscovery” of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely. This review will give an overview of recent studies and emerging concepts of how the cellular components of the innate immune system participate in the immune response to solid organ transplantation. These important studies highlight the complex interplay between diverse cells of the immune response and provide the basis for optimal strategies of tolerance induction.

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“…Alloantigen-specific T cell priming of heart graft recipients was assessed by enumerating donor-specific T cells producing IFN-␥ and IL-4 by ELISPOT assay, as previously described (20,22). Briefly, ELISPOT plates were coated with purified rat anti-mouse IFN-␥ or IL-4 mAb (BD Pharmingen), incubated overnight at 4°C, and then blocked with 1% BSA/PBS.…”

Section: Elispot Assaysmentioning

confidence: 99%

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Nozaki

Amano

Bickerstaff

et al. 2007

The Journal of Immunology

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Rejected MHC-mismatched cardiac allografts in CCR5−/− recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5−/− recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5−/− (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-γ, whereas CD4 T cells producing IL-4 were increased in CCR5−/− recipients. Numbers of donor-reactive CD8 T cells producing IFN-γ were reduced 60% in CCR5−/− recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5−/− allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1−/− recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5−/− recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in μMT−/−/CCR5−/− recipients. These results indicate that the donor-specific Ab produced in CCR5−/− heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.

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Inhibition of Polymorphonuclear Leukocyte–Mediated Graft Damage Synergizes With Short-Term Costimulatory Blockade to Prevent Cardiac Allograft Rejection

Cited by 94 publications

References 35 publications

Interleukin-17 Promotes Early Allograft Inflammation

Interleukin-17 Promotes Early Allograft Inflammation

The Innate Immune System in Allograft Rejection and Tolerance

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

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