Type 1 IFN Mediates Cross-Talk between Innate and Adaptive Immunity That Abrogates Transplantation Tolerance

Thornley, Thomas B.; Phillips, Nancy E.; Beaudette-Zlatanova, Britte C.; Markees, Thomas G.; Bahl, Kapil; Brehm, Michael A.; Shultz, Leonard D.; Kurt-Jones, Evelyn A.; Mordes, John P.; Welsh, Raymond M.; Rossini, Aldo A.; Greiner, Dale L.

doi:10.4049/jimmunol.179.10.6620

Cited by 68 publications

(71 citation statements)

References 57 publications

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“…Recently, type I IFNs have been reported to mediate the prevention of skin allograft acceptance by LPS and polyinosinic:polycytidylic acid by reducing the deletion of alloreactive CD8 ϩ T cells necessary for graft acceptance (42). We have extended these findings to a microbial infection and demonstrate a correlation between LM-induced IFN-␤ production and the prevention of allograft acceptance, the necessity of IFN␣R1 signaling for LM to prevent anti-CD154/DST-induced graft survival, and the sufficiency of type I IFN to prevent anti-CD154/ DST-mediated graft survival.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Wang¹,

Chen

Ahmed³

et al. 2008

The Journal of Immunology

101

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Exposure to certain viruses and parasites has been shown to prevent the induction of transplantation tolerance in mice via the generation of cross-reactive memory T cell responses or the induction of bystander activation. Bacterial infections are common in the perioperative period of solid organ allograft recipients in the clinic, and correlations between bacterial infections and acute allograft rejection have been reported. However, whether bacterial infections at the time of transplantation have any effect on the generation of transplantation tolerance remains to be established. We used the Gram-positive intracellular bacterium Listeria monocytogenes (LM) as a model pathogen because its effects on immune responses are well described. Perioperative LM infection prevented cardiac and skin allograft acceptance induced by anti-CD154 and donor-specific transfusion in mice. LM-mediated rejection was not due to the generation of cross-reactive T cells and was largely independent of signaling via MyD88, an adaptor for most TLRs, IL-1, and IL-18. Instead, transplant rejection following LM infection was dependent on the expression of the phagosome-lysing pore former listeriolysin O and on type I IFN receptor signaling. Our results indicate that bacterial exposure at the time of transplantation can antagonize tolerogenic regimens by enhancing alloantigen-specific immune responses independently of the generation of cross-reactive memory T cells.

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Section: Discussionmentioning

confidence: 99%

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Wang¹,

Chen

Ahmed³

et al. 2008

The Journal of Immunology

101

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“…2,3 These adjuvants include agonists of Toll-like receptors 3 and 4, which might induce antigen-independent activation and maturation of B cells and T cells. 4,5 Most patients in the study by Scharpé and colleagues were on relatively conventional immunosuppression regimens consisting of a calcineurin inhibitor (tacrolimus or ciclosporin), an antiproliferative agent (azathioprine or mycophenolate mofetil) and a corticosteroid (methylprednisolone). Patients on newer immunosuppressive agents, such as sirolimus, alemtuzumab or belatacept, and those on protocols that avoid steroids or calcineurin inhibitors, might have markedly different vaccine responses and adverse effect rates.…”

Section: O M M E N Ta Rymentioning

confidence: 98%

Safety and efficacy of influenza vaccination in renal transplant recipients

Zand

2008

Nat Rev Nephrol

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This Practice Point commentary discusses Scharpé et al.'s single-center, nonrandomized, prospective trial of influenza vaccination in renal transplant recipients. In total, 165 transplant recipients and 41 healthy volunteers were vaccinated with a standard inactivated trivalent influenza vaccine (containing strains of the A/H1N1, A/H3N2 and B viruses). No rejection episodes or other adverse events were reported in either group. Influenza-specific antibody titers increased in renal transplant recipients following vaccination, as measured by comparison of pre-vaccination and post-vaccination seroprotection and seroresponse rates. This commentary discusses the limitations of the trial, and urges caution in extending the conclusions drawn by Scharpé et al. regarding the safety of the trivalent, non-adjuvant-containing influenza vaccine to newer adjuvant-assisted vaccines. Annual vaccination for influenza by use of the trivalent vaccine strategy without adjuvant should, however, be standard of care for all stable renal transplant recipients who do not have clinical contraindications.

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“…45,46 Furthermore, in studies in both patients and experimental models in which tolerance has been achieved investigators have demonstrated that type I-IFN signaling after either viral infection or endogenous administration can initiate rejection. 47,48 Conversely, type I-IFN blockage in conjunction with immunosuppression can prolong allograft survival. 49 Therefore, although the role of type I-IFN after solid-organ transplantation still remains controversial, a majority of studies suggest that signaling enhances alloreactive responses.…”

mentioning

confidence: 99%

Type I-IFNs control GVHD and GVL responses after transplantation

Robb

Kreijveld

Kuns

et al. 2011

Blood

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Although the effects of type II-IFN (IFN-␥) on GVHD and leukemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-␣/␤) remain unclear. We investigated this using type I-IFN receptordeficient mice and exogenous IFN-␣ administration in established models of GVHD and GVL. Type I-IFN signaling in host tissue prevented severe colontargeted GVHD in CD4-dependent models of GVHD directed toward either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4 ؉ T-cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signaling in hematopoietic tissue. Consistent with this finding, administration of IFN-␣ during conditioning inhibited donor CD4 ؉ proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signaling was intact in the host or donor, respectively. This finding reflected the ability of type I-IFN to both sensitize host target tissue/leukemia to cell-mediated cytotoxicity and augment donor CTL function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of the cytokine after BM transplantation could be studied prospectively in patients at high risk of relapse. (Blood. 2011;118(12):3399-3409) IntroductionAlthough allogeneic BM transplantation is curative therapy for a majority of hematologic malignancies, its application has been limited by the development of GVHD. GVHD is the result of immunologic damage to the host tissue by alloreactive T cells from the incoming donor graft. Unfortunately, the development of detrimental GVHD is closely intertwined with therapeutic GVL responses. GVL responses are important for eradication of residual host malignancy and are primarily mediated by alloreactive donor T and natural killer (NK) cells. Therapeutic approaches to separate these phenomena are urgently needed.The IFNs were first discovered as a result of their capacity to confer cell resistance to viral infection. 1 There are 2 distinct IFN types, type I and type II, and although both groups induce antiviral defense mechanisms in cells, primarily by limiting replication, they exhibit distinct immunologic properties. After allograft rejection, it is well established that the type II-IFN, IFN-␥, is a dominant Th1 cytokine, exerting pleotropic effects on both hematopoietic and nonhematopoietic cells. Importantly, IFN-␥ has differential effects on both donor and host tissue, with a protective role dominating within GVHD of the lung and pathogenic effects dominating in the gastrointestinal tract. [2][3][4] In addition, the cellular subsets producing IFN␥ and the timing of production may also impact the effect of the cytokine after BM transplantation. 5 In contrast, the role of type I-IFN after BM transplantation remains largely unknown.All type I-IFNs act through the same receptor, which is composed of 2 subunits, IFNAR...

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Type 1 IFN Mediates Cross-Talk between Innate and Adaptive Immunity That Abrogates Transplantation Tolerance

Cited by 68 publications

References 57 publications

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Safety and efficacy of influenza vaccination in renal transplant recipients

Type I-IFNs control GVHD and GVL responses after transplantation

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