IL-5 and eosinophils mediate the rejection of fully histoincompatible vascularized cardiac allografts: regulatory role of alloreactive CD8+ T lymphocytes and IFN-γ

Previous work on blockade of CD40-CD40 ligand interaction in mice and primates with anti-CD40 ligand mAbs has resulted in a moderate prolongation of allograft survival without the development of true allograft tolerance. In this study, we show in rats that adenovirus-mediated gene transfer of CD40Ig sequences into the graft resulted in prolonged (>200 days) expression of CD40Ig and in long-term (>300 days) survival. Recipients expressing CD40Ig displayed strongly (>90%) inhibited mixed leukocyte reactions and alloantibody production at early (days 5 and 17) and late time points (>100 day) after transplantation, but showed limited inhibition of leukocyte infiltration and cytokine production as evaluated by immunohistology at early time points (day 5). Recipients of long-surviving hearts showed donor-specific hyporesponsiveness since acceptance of second cardiac allografts was donor specific. Nevertheless, long-term allografts (>100 days) displayed signs of chronic rejection vasculopathy. Occluded vessels showed leukocyte infiltration, mainly composed of CD4+ and CD8+ cells, macrophages, and mast cells. These recipients also showed antidonor CTL activity. Recipients expressing CD40Ig did not show nonspecific immunosuppression, as they were able to mount anticognate immune responses that were partially inhibited at early time points and were normal thereafter. We conclude that gene transfer-mediated expression of CD40Ig resulted in a highly efficient inhibition of acute heart allograft rejection in rats. This treatment induced donor-specific inhibition of certain alloreactive mechanisms in the short-, but not the long-term, which resulted in long-term survival of allografts concomitant with the development of chronic rejection.

Section: Discussionmentioning

confidence: 99%

“…Several leukocyte types have been implicated in the development of chronic rejection (2,25,(33)(34)(35). Among them, CD8 ϩ cells and eosinophils have been shown to be responsible for chronic rejection in models of CD40-CD40L blockade (23,25).…”

Section: Long-surviving Grafts Expressing Cd40ig Displayed Chronic Rementioning

confidence: 98%

Prolonged Blockade of CD40-CD40 Ligand Interactions by Gene Transfer of CD40Ig Results in Long-Term Heart Allograft Survival and Donor-Specific Hyporesponsiveness, But Does Not Prevent Chronic Rejection

Guillot

Guillonneau

Mathieu

et al. 2002

“…In the absence of CD8 ϩ T cell alloreactivity, such as in the response of B6 mice to MHC class II-disparate Bm12 skin grafts, numerous eosinophils are found in the inflammatory infiltrate. Other studies similarly indicate that, in the absence of CD8 ϩ T cell activation or IFN-␥R expression, the response of alloreactive CD4 ϩ T cells is T H 2 biased and promotes eosinophilic inflammation (72,73). As in allergic-type inflammatory diseases, eosinophils can cause tissue damage through the release of highly cationic granule proteins and the production of several cytokines that further promote inflammation and T H 2 polarization (such as IL-1, IL-3, IL-4, IL-5, IL-8, and TNF-␣).…”

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

confidence: 94%

The Innate Immune System in Allograft Rejection and Tolerance

LaRosa

Rahman

Turka

2007

168

121

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.

“…CD4 ϩ or CD8 ϩ T cell purifications were realized with LN cells from 4-wk-old wild-type or IFN-␥ Ϫ/Ϫ BALB/c mice that were first passed over a nylon wool column; the nonadherent fraction was further purified by complement-mediated lysis as previously described (15).…”

Section: Mixed Lymphocyte Culturementioning

confidence: 84%

“…This was confirmed by the observation that suppression of IL-4 production in this system decreased from 82 to 38% when anti-H-2K k mAb was added to the MLC. Since IFN-␥ was found to mediate inhibition of Th2 responses by CD8 ϩ T cells in other systems (15,(21)(22)(23), we repeated this MLC with CD8 ϩ T cells from IFN-␥-deficient mice. As shown in Fig.…”

Section: Cd8 ϩ T Cells From Tolerant Mice Regulate Cd4 ϩ T Cellmediatmentioning

confidence: 94%

CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization

Adams

Nagy

Paulart

et al. 2003

Self Cite

Transplantation tolerance induced by neonatal injection of semiallogeneic spleen cells is associated in several strain combinations with a pathological syndrome caused by Th2 differentiation of donor-specific CD4+ T lymphocytes. We investigated the role of host CD8+ T cells in the regulation of this Th2 pathology. IgE serum levels and eosinophilia significantly increased in BALB/c mice neonatally injected with (A/J × BALB/c)F1 spleen cells when CD8+ T cells were depleted by administration of anti-CD8 mAb or when β2-microglobulin-deficient mice were used as recipients. In parallel, increased serum levels of IL-5 and IL-13 were measured in blood of tolerant CD8+ T cell-deficient mice. Whereas neonatally injected mice were unable to generate anti-donor cytotoxic effectors, their CD8+ T cells were as efficient as control CD8+ T cells in reducing the severity of Th2 pathology and in restoring donor-specific cytotoxicity in vitro after in vivo transfer in β2-microglobulin-deficient mice. Likewise, CD8+ T cells from control and tolerant mice equally down-regulated the production of Th2 cytokines by donor-specific CD4+ T cells in vitro. The regulatory activity of CD8+ T cells depended on their secretion of IFN-γ for the control of IL-5 production but not for IL-4 or IL-13. Finally, we found that CD8+ T cells from 3-day-old mice were already able to down-regulate IL-4, IL-5, and IL-13 production by CD4+ T cells. We conclude that regulatory CD8+ T cells controlling Th2 responses are functional in early life and escape neonatal tolerization.