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


CONCLUSIONS
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.
Jiang
Jifu
J
Multi-Organ Transplant Program, London Health Sciences Centre-University Hospital, London, Ontario, Canada.
Arp
Jacqueline
J
Kubelik
Dalibor
D
Zassoko
Roman
R
Liu
Weihua
W
Wise
Yishai
Y
Macaulay
Colin
C
Garcia
Bertha
B
McFadden
Grant
G
Lucas
Alexandra R
AR
Wang
Hao
H
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D015536:Down-Regulation; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D007166:Immunosuppressive Agents; D008297:Male; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D015843:Serpins / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000235:genetics*; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D015843:Serpins; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016572:Cyclosporine