Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment

Jifu Jiang, Jacqueline Arp, Dalibor Kubelik, Roman Zassoko, Weihua Liu, Yishai Wise, Colin MacAulay, Bertha Garcia, Douglas McFadden, Alexandra R. Lucas, Hao Wang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

BACKGROUND. Innate immunity provides obstacles to successful organ transplantation, which cannot be prevented by cyclosporine (CsA). Here we have determined the potential of a myxoma viral serpin, Serp-1, with proven anti-inflammatory and antiatherogenic actions, to modulate innate immunity and contribute synergistically with CsA in the prevention of acute cardiac allograft rejection. METHODS. Brown-Norway rat hearts were heterotopically transplanted into Lewis rats and given either a monotherapy treatment of Serp-1, a subtherapeutic dose of CsA, or the two drugs in combination. RESULTS. A brief treatment of Serp-1 alone, or a subtherapeutic dose of CsA, resulted in a marked decrease in intragraft macrophage infiltration and downregulation of toll-like receptor (TLR)-2, TLR4 and MyD88 at 48 hours posttransplantation, which was associated with significantly reduced numbers of mature dendritic cells. A significant reduction in intragraft T-lymphocyte infiltration was observed with both Serp-1 monotherapy and Serp-1 and CsA combination therapy, with the combination treatment achieving indefinite graft survival (>100 days) with normal histology. The CsA monotherapy group displayed partially reduced lymphocyte infiltration compared to the untreated controls, but failed to inhibit early innate immune graft recognition events such as macrophage infiltration and TLR 2, TLR4, and MyD88, and was ultimately unsuccessful in preventing rejection (36.3±7.8 days). CONCLUSION. Observed suppressive effects of Serp-1 on early innate immune response components such as TLR-2 and 4, and on adaptive responses such as T-cell intragraft infiltration suggests that Serp-1 may modulate the transition from innate to adaptive immunity, exhibiting a synergistic effect on allograft survival when used in combination with a subtherapeutic dose of CsA.

Original languageEnglish (US)
Pages (from-to)1158-1167
Number of pages10
JournalTransplantation
Volume84
Issue number9
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Toll-Like Receptor 2
Toll-Like Receptor 4
Serine Proteinase Inhibitors
Allografts
Down-Regulation
Innate Immunity
Therapeutics
Macrophages
Serpins
T-Lymphocytes
Myxoma
Organ Transplantation
Adaptive Immunity
Graft Survival
Drug Combinations
Dendritic Cells
Cyclosporine
Histology
Anti-Inflammatory Agents
Lymphocytes

Keywords

  • Acute rejection
  • Innate immunity
  • Serp-1
  • Serpin
  • Toll-like receptor
  • Transplantation
  • Virus

ASJC Scopus subject areas

  • Transplantation

Cite this

Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment. / Jiang, Jifu; Arp, Jacqueline; Kubelik, Dalibor; Zassoko, Roman; Liu, Weihua; Wise, Yishai; MacAulay, Colin; Garcia, Bertha; McFadden, Douglas; Lucas, Alexandra R.; Wang, Hao.

In: Transplantation, Vol. 84, No. 9, 01.11.2007, p. 1158-1167.

Research output: Contribution to journalArticle

Jiang, Jifu ; Arp, Jacqueline ; Kubelik, Dalibor ; Zassoko, Roman ; Liu, Weihua ; Wise, Yishai ; MacAulay, Colin ; Garcia, Bertha ; McFadden, Douglas ; Lucas, Alexandra R. ; Wang, Hao. / Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment. In: Transplantation. 2007 ; Vol. 84, No. 9. pp. 1158-1167.
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AU - Arp, Jacqueline

AU - Kubelik, Dalibor

AU - Zassoko, Roman

AU - Liu, Weihua

AU - Wise, Yishai

AU - MacAulay, Colin

AU - Garcia, Bertha

AU - McFadden, Douglas

AU - Lucas, Alexandra R.

AU - Wang, Hao

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N2 - BACKGROUND. Innate immunity provides obstacles to successful organ transplantation, which cannot be prevented by cyclosporine (CsA). Here we have determined the potential of a myxoma viral serpin, Serp-1, with proven anti-inflammatory and antiatherogenic actions, to modulate innate immunity and contribute synergistically with CsA in the prevention of acute cardiac allograft rejection. METHODS. Brown-Norway rat hearts were heterotopically transplanted into Lewis rats and given either a monotherapy treatment of Serp-1, a subtherapeutic dose of CsA, or the two drugs in combination. RESULTS. A brief treatment of Serp-1 alone, or a subtherapeutic dose of CsA, resulted in a marked decrease in intragraft macrophage infiltration and downregulation of toll-like receptor (TLR)-2, TLR4 and MyD88 at 48 hours posttransplantation, which was associated with significantly reduced numbers of mature dendritic cells. A significant reduction in intragraft T-lymphocyte infiltration was observed with both Serp-1 monotherapy and Serp-1 and CsA combination therapy, with the combination treatment achieving indefinite graft survival (>100 days) with normal histology. The CsA monotherapy group displayed partially reduced lymphocyte infiltration compared to the untreated controls, but failed to inhibit early innate immune graft recognition events such as macrophage infiltration and TLR 2, TLR4, and MyD88, and was ultimately unsuccessful in preventing rejection (36.3±7.8 days). CONCLUSION. Observed suppressive effects of Serp-1 on early innate immune response components such as TLR-2 and 4, and on adaptive responses such as T-cell intragraft infiltration suggests that Serp-1 may modulate the transition from innate to adaptive immunity, exhibiting a synergistic effect on allograft survival when used in combination with a subtherapeutic dose of CsA.

AB - BACKGROUND. Innate immunity provides obstacles to successful organ transplantation, which cannot be prevented by cyclosporine (CsA). Here we have determined the potential of a myxoma viral serpin, Serp-1, with proven anti-inflammatory and antiatherogenic actions, to modulate innate immunity and contribute synergistically with CsA in the prevention of acute cardiac allograft rejection. METHODS. Brown-Norway rat hearts were heterotopically transplanted into Lewis rats and given either a monotherapy treatment of Serp-1, a subtherapeutic dose of CsA, or the two drugs in combination. RESULTS. A brief treatment of Serp-1 alone, or a subtherapeutic dose of CsA, resulted in a marked decrease in intragraft macrophage infiltration and downregulation of toll-like receptor (TLR)-2, TLR4 and MyD88 at 48 hours posttransplantation, which was associated with significantly reduced numbers of mature dendritic cells. A significant reduction in intragraft T-lymphocyte infiltration was observed with both Serp-1 monotherapy and Serp-1 and CsA combination therapy, with the combination treatment achieving indefinite graft survival (>100 days) with normal histology. The CsA monotherapy group displayed partially reduced lymphocyte infiltration compared to the untreated controls, but failed to inhibit early innate immune graft recognition events such as macrophage infiltration and TLR 2, TLR4, and MyD88, and was ultimately unsuccessful in preventing rejection (36.3±7.8 days). CONCLUSION. Observed suppressive effects of Serp-1 on early innate immune response components such as TLR-2 and 4, and on adaptive responses such as T-cell intragraft infiltration suggests that Serp-1 may modulate the transition from innate to adaptive immunity, exhibiting a synergistic effect on allograft survival when used in combination with a subtherapeutic dose of CsA.

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