Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance

Chalermskulrat, Worakij; McKinnon, Karen P.; Brickey, W. June; Neuringer, Isabel P.; Park, R C; Sterka, David; Long, B.R.; McNeillie, Patrick; Noelle, Randolph J.; Ting, Jenny P.Y.; Aris, Robert M.

doi:10.1136/thx.2005.047316

Cited by 15 publications

(12 citation statements)

References 37 publications

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“…On the other hand, MR1 treatment promotes some donor-specific tolerance effect since mice transplanted with a vascularized skin allograft subsequently accept heart transplants from the same donor but not a third-party one. Transplant tolerance has been previously achieved via MR1 treatment combined with donor specific transfusion (DST) (42-44). In this model, tolerance was attributed to regulatory T cells (Tregs) activated in an indirect fashion (45).…”

Section: Discussionmentioning

confidence: 99%

Primary Vascularization of Allografts Governs Their Immunogenicity and Susceptibility to Tolerogenesis

Kant

Akiyama

Tanaka

et al. 2013

The Journal of Immunology

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We investigated the influence of allograft primary vascularization on alloimmunity, rejection and tolerance in mice. First, we showed that fully allogeneic primarily vascularized and conventional skin transplants were rejected at the same pace. Remarkably, however, short-term treatment of mice with anti-CD40L antibodies achieved long-term survival of vascularized skin and cardiac transplants but not conventional skin grafts. Non-vascularized skin transplants triggered vigorous direct and indirect pro-inflammatory type 1 T cell responses (IL-2 and γIFN) while primarily-vascularized skin allografts failed to trigger a significant indirect alloresponse. Similar lack of indirect alloreactivity was also observed after placement of different vascularized organ transplants including hearts and kidneys while hearts placed under the skin (non-vascularized) triggers potent indirect alloresponses. Altogether, these results suggest that primary vascularization of allografts is associated with lack of indirect T cell alloreactivity. Finally, we show that long-term survival of vascularized skin allografts induced by anti-CD40L antibodies was associated with a combined lack of indirect alloresponse and a shift of the direct alloresponse towards a type 2 cytokine (IL-4, IL-10) secretion pattern but no activation/expansion of regulatory T cells. Therefore, primary vascularization of allografts governs their immunogenicity and tolerogenicity.

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Section: Discussionmentioning

confidence: 99%

Primary Vascularization of Allografts Governs Their Immunogenicity and Susceptibility to Tolerogenesis

Kant

Akiyama

Tanaka

et al. 2013

The Journal of Immunology

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“…In contrast, the CD40 ligand (CD40L, CD154)/CD40 costimulation pathway appears critical for murine OAD pathogenesis, because CD154 Ϫ/Ϫ airway allograft recipients are OAD resistant (39). In addition, two recent studies using anti-CD154 Ab treatment alone or in combination with donor spleen cell transfusion significantly blocked OAD development (55,56). However, the mechanisms leading to resistance to OAD in the absence of CD154/CD40 costimulation remain undefined, although recent studies in a skin transplant model suggest that CD4 ϩ CD25 ϩ regulatory T cells may play an important role (57).…”

Section: Costimulation Blockade In Airway Transplantmentioning

confidence: 99%

Human and Murine Obliterative Bronchiolitis in Transplant

McDyer¹

2007

Proceedings of the American Thoracic Society

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Obliterative bronchiolitis is a devastating illness that limits the longterm success of lung transplantation. Its high prevalence and overall poor response to current therapeutic measures demands further research to elucidate pathogenic mechanisms. Toward this goal, there is a role for animal models to study the mechanisms of obliterative bronchiolitis, such as the murine heterotopic tracheal allograft model. This review compares the tracheal allograft model to human obliterative bronchiolitis pathology and highlights the important mechanisms of airway rejection described using this model. Although certain limitations exist, the pursuit of proof-of-concept studies in this model, as well as other animal models, can provide the basis for genetic and cellular translational human studies directed toward post-transplant obliterative bronchiolitis pathogenesis. To meet these challenges, we call for the establishment of a National Institutes of Health-supported Lung Transplant Network to better orchestrate translational research efforts in obliterative bronchiolitis pathogenesis and treatment, and to advance the field of lung transplantation.

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“…To address this, we chose to use the mouse complete major histocompatibility complex (MHC)-mismatched HTT model in which allogeneic grafts develop OAD by day 28 following marked airway graft infiltration by alloreactive CD8 + T-cells, as this model directly evaluates airway obliteration that is spared in the mouse orthotopic lung transplant model (7–9). Because costimulation blockade is an effective strategy for establishing transplantation tolerance in several experimental transplant models including airway transplant (10–13), we first evaluated a tolerance protocol using DST and anti-CD154 therapy and observed significant lack of OAD development in airway grafts that correlated with an absence of alloreactive CD8 + T-cell responses. Several studies have demonstrated the capacity of toll-like receptor (TLR) agonists to abrogate costimulation blockade-induced allograft acceptance, including the TLR3 agonist dsRNA or poly(I:C), a functional analog of viral RNA (14, 15).…”

Section: Introductionmentioning

confidence: 99%

Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration

Miller

Shah

Orens

et al. 2013

The Journal of Heart and Lung Transplantation

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BACKGROUND Respiratory RNA viruses are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRS), however the immune mechanisms that regulate airway obliteration remain incompletely understood. METHODS Using the mouse heterotopic tracheal transplant (HTT) model of obliterative airway disease (OAD), we studied the role of dsRNA using (polyinosinic:polycytidylic acid; poly(I:C)), a synthetic analog of viral dsRNA, in abrogating airway allograft tolerance established with donor-specific transfusion (DST) and anti-CD154 mAb therapy. RESULTS Wild-type (WT) B6 recipients of accepted BALB/c airway grafts demonstrated significantly reduced intragraft CD8+ T-cells with markedly impaired allospecific IFN-γ and TNF-α secretion, uncoupled from an activated phenotype and evidence of proliferation. Administration of poly(I:C) to DST/anti-CD154-treated recipients restored OAD pathology and CD8+ alloeffector responses to levels observed in untreated mice. However, B6 IFNαβR−/− recipients were resistant to the abrogation of tolerance mediated by poly(I:C) and did not develop CD8+ alloeffector responses or OAD. Further, adoptive transfers of either WT CD8+ T-cells or CD11c+ dendritic cells (DC) alone into B6 IFNαβR−/− recipients treated with poly(I:C) and DST/anti-CD154 were incapable of abrogating airway graft tolerance. CONCLUSIONS Together, these data indicate abrogation of DST/anti-CD154-induced airway allograft tolerance via dsRNA requires type-I IFN responsiveness for mouse airway obliteration.

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Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance

Cited by 15 publications

References 37 publications

Primary Vascularization of Allografts Governs Their Immunogenicity and Susceptibility to Tolerogenesis

Primary Vascularization of Allografts Governs Their Immunogenicity and Susceptibility to Tolerogenesis

Human and Murine Obliterative Bronchiolitis in Transplant

Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration

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