Chronic heart allograft rejection in rats demonstrates a dynamic interplay between IFN-γ and IL-10 producing T cells

Köksoy, Sadi; Kakoulidis, Thanos P.; Shirwan, Haval

doi:10.1016/j.trim.2004.03.001

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…Furthermore, it is unclear why the CD4 ϩ CD25 ϩ T reg cells were ineffective in preventing chronic rejection in primary recipients. It is conceivable that by the time T reg cells were generated in the primary recipients, damage to the grafts had already occurred and thus chronic rejection might be the end result of the inability to repair the damaged grafts' endothelium (30).…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

et al. 2005

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“…Two hrs later, cultures were supplemented with Golgi Plug (1 μl/ml, BD Bioscience) and incubated for an additional 2.5 h. Cells were then stained with fluorescent conjugated antibodies against rat CD4, CD8, and IFN-γ, and analyzed by flow cytometry as previously described (27). …”

Section: Methodsmentioning

confidence: 99%

Induction of Tolerance to Cardiac Allografts Using Donor Splenocytes Engineered to Display on Their Surface an Exogenous Fas Ligand Protein

Yolcu

Lacelle

et al. 2008

The Journal of Immunology

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The critical role played by Fas ligand (FasL) in immune homeostasis renders this molecule an attractive target for immunomodulation to achieve tolerance to auto- and transplantation Ags. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging. Therefore, we tested the efficacy of donor splenocytes rapidly and efficiently engineered to display on their surface a chimeric form of FasL protein (SA-FasL) for tolerance induction to cardiac allografts. The i.p. injection of ACI rats with Wistar-Furth rat splenocytes displaying SA-FasL on their surface resulted in tolerance to donor, but not F344 third-party cardiac allografts. Tolerance was associated with apoptosis of donor reactive T effector cells and induction/expansion of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Treg cells played a critical role in the observed tolerance as adoptive transfer of sorted Treg cells from long-term graft recipients into naive unmanipulated ACI rats resulted in indefinite survival of secondary Wistar-Furth grafts. Immunomodulation with allogeneic cells rapidly and efficiently engineered to display on their surface SA-FasL protein provides an effective and clinically applicable means of cell-based therapy with potential application to regenerative medicine, transplantation, and autoimmunity.

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“…In another study from the Martinez’s group, the existence of a non-classical pathway of liver allograft rejection was shown to involve IL-5 and graft infiltrating eosinophils secreting a series of cytotoxic mediators including eosinophil peroxidase, eosinophil-derived neurotoxin, eosinophil cationic protein, and major basic protein (MB; Martinez et al, 1993). In addition, a number of studies from us and others have provided direct evidence demonstrating that alloreactive TH2 cells activated through the indirect allorecognition pathway can trigger chronic allograft vasculopathy and tissue fibrosis in MHC class I-mismatched transplanted hearts (Shirwan, 1999; Mhoyan et al, 2003; Koksoy et al, 2004; Illigens et al, 2009). At the same time, it has been reported that, in models in which acute rejection had been suppressed, eosinophilic graft infiltration could induce fibrosis through their production of TGF-β, a key mediator of extracellular matrix remodeling (Goldman et al, 2001).…”

Section: Cells Of the Innate Immune Systemmentioning

confidence: 99%

Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

Bénichou¹,

Tonsho²,

Tocco³

et al. 2012

Front. Immun.

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The development of immunosuppressive drugs to control adaptive immune responses has led to the success of transplantation as a therapy for end-stage organ failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained in clinical significance as mounting evidence now indicates that innate immune responses play important roles in the acute and chronic rejection of whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and prevent tolerance induction. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejection and interferes with tolerance. In summary, the conventional wisdom that the innate immune system is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients.

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Chronic heart allograft rejection in rats demonstrates a dynamic interplay between IFN-γ and IL-10 producing T cells

Cited by 11 publications

References 35 publications

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Tolerance to Rat Heart Grafts Induced by Intrathymic Immunomodulation Is Mediated by Indirect Recognition Primed CD4+CD25+ Treg Cells

Induction of Tolerance to Cardiac Allografts Using Donor Splenocytes Engineered to Display on Their Surface an Exogenous Fas Ligand Protein

Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

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