Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

L. A. DeBruyne, K. Li, S. Y. Chan, L. Qin, D. K. Bishop, J. S. Bromberg

Research output: Contribution to journalArticlepeer-review

Abstract

The gene encoding the immunosuppressive cytokine viral interleukin-10 (vIL-10) was introduced into BALB/c (H-2(d)) vascularized cardiac allografts by perfusing the graft vasculature with DNA-liposome complexes, utilizing the experimental cationic lipid γAP DLRIE/DOPE and a plasmid encoding vlL-10 under the control of the HCMVie promoter. The DNA to lipid ratio and DNA dose were critical factors in obtaining optimal biologic effects. Gene transfer of vIL-10 with a 3:1 DNA to lipid weight ratio using 375 μg DNA significantly prolonged allograft survival in MHC-mismatched C57BL/6 (H-2b) recipients (16.00 days) compared with both unmodified allografts (8.14 days) and vIL-10 anti-sense controls (8.28 days). Enhanced graft survival was specific to vIL-10 expression since treatment with anti-sense plasmid or anti-vIL-10 monoclonal antibody (mAb) abrogated the effect. Prolonged survival was associated with a novel histology characterized by a moderate mono-nuclear infiltrate, edema, and diffuse fibrillar/collagen deposition in the interstitium. Despite these morphologic changes, myocytes remained viable and vessels were patent. Limiting dilution analysis revealed transient infiltration of IL-2 secreting, donor-reactive, helper T lymphocytes (HTL) and cytotoxic T lymphocytes (CTL) in vIL-10 expressing grafts on day 7, that decreased significantly by day 14. Similarly, vIL-10 gene transfer inhibited the accumulation of donor-specific HTL and CTL in the spleen, compared with antisense controls. Prolonged survival was also associated with a marked decrease in IgM and IgG alloantibody production, with little to no IgG isotype switching. These results show that viral IL-10 gene transfer inhibits graft rejection in a clinically relevant model by inhibiting donor-specific cellular and humoral immune responses.

Original languageEnglish (US)
Pages (from-to)1079-1087
Number of pages9
JournalGene therapy
Volume5
Issue number8
DOIs
StatePublished - 1998
Externally publishedYes

Keywords

  • Gene transfer
  • Immunotherapy
  • Transplantation
  • Viral interleukin-10 (vIL-10)

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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