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CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.

Corbascio, Matthias; Ekstrand, Helene; Österholm, Cecilia LU ; Qi, Zhongquan LU ; Simanaitis, Mecislovas; Larsen, Christian P; Pearson, Thomas C; Riesbeck, Kristian LU and Ekberg, Henrik (2002) In Transplant Immunology 10(1). p.55-61
Abstract
CTLA4Ig and anti-LFA-1 are members of a new generation of immunomodulatory drugs which inhibit important signaling pathways in T cell activation. Both substances target molecules which have pivitol functions in the activation of CD4+ and CD8+ T cells and have been theorized to have an interdependent relationship. These drugs have been used independently in various treatment regimens and have shown great promise in prolonging the survival of allografts. In order to test whether these substances have synergistic or potentiating effects when combined, we performed mixed lymphocyte reactions, skin transplantation and vascularised heterotopic heart transplantation in the Balb/c (H-2(d)) to C3H/HeJ (H-2(k)) strain combination. When anti-LFA-1... (More)
CTLA4Ig and anti-LFA-1 are members of a new generation of immunomodulatory drugs which inhibit important signaling pathways in T cell activation. Both substances target molecules which have pivitol functions in the activation of CD4+ and CD8+ T cells and have been theorized to have an interdependent relationship. These drugs have been used independently in various treatment regimens and have shown great promise in prolonging the survival of allografts. In order to test whether these substances have synergistic or potentiating effects when combined, we performed mixed lymphocyte reactions, skin transplantation and vascularised heterotopic heart transplantation in the Balb/c (H-2(d)) to C3H/HeJ (H-2(k)) strain combination. When anti-LFA-1 and CTLA4Ig were combined at low doses, there was a substantial inhibition of lymphocyte proliferation. When each drug was used as a mono-therapy in skin graft recipients, there was no significant effect on median graft survival (anti-LFA-1, 15 days; CTLA4Ig, 16 days) when compared to untreated controls (13 days), whereas a combination of anti-LFA-1 and CTLA4Ig extended graft survival significantly to 32 days. Untreated vascularised heart grafts rejected at a median of 8 days, CTLA4Ig-treated mice rejected at a median time of 79 days and anti-LFA-1-treated mice rejected at 43 days (n = 9). When CTLA4Ig and anti-LFA-1 were combined, all animals had functioning heart grafts at 100 days after transplantation. Histological analysis of combined-therapy hearts showed no signs or only minor changes associated with chronic rejection. In conclusion, these results indicate a synergistic effect of combining anti-LFA-1 with CTLA4Ig in inhibiting lymphocyte proliferation and prolonging the survival of fully MHC-mismatched allografts. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Transplant Immunology
volume
10
issue
1
pages
55 - 61
publisher
Elsevier
external identifiers
  • wos:000177373000008
  • pmid:12182466
  • scopus:0036023131
ISSN
1878-5492
DOI
10.1016/S0966-3274(02)00014-X
language
English
LU publication?
yes
id
9bef29b7-4381-4b3b-9be8-05ff2b0c2ef8 (old id 109973)
alternative location
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12182466&ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
date added to LUP
2007-06-27 15:52:16
date last changed
2017-03-12 03:28:16
@article{9bef29b7-4381-4b3b-9be8-05ff2b0c2ef8,
  abstract     = {CTLA4Ig and anti-LFA-1 are members of a new generation of immunomodulatory drugs which inhibit important signaling pathways in T cell activation. Both substances target molecules which have pivitol functions in the activation of CD4+ and CD8+ T cells and have been theorized to have an interdependent relationship. These drugs have been used independently in various treatment regimens and have shown great promise in prolonging the survival of allografts. In order to test whether these substances have synergistic or potentiating effects when combined, we performed mixed lymphocyte reactions, skin transplantation and vascularised heterotopic heart transplantation in the Balb/c (H-2(d)) to C3H/HeJ (H-2(k)) strain combination. When anti-LFA-1 and CTLA4Ig were combined at low doses, there was a substantial inhibition of lymphocyte proliferation. When each drug was used as a mono-therapy in skin graft recipients, there was no significant effect on median graft survival (anti-LFA-1, 15 days; CTLA4Ig, 16 days) when compared to untreated controls (13 days), whereas a combination of anti-LFA-1 and CTLA4Ig extended graft survival significantly to 32 days. Untreated vascularised heart grafts rejected at a median of 8 days, CTLA4Ig-treated mice rejected at a median time of 79 days and anti-LFA-1-treated mice rejected at 43 days (n = 9). When CTLA4Ig and anti-LFA-1 were combined, all animals had functioning heart grafts at 100 days after transplantation. Histological analysis of combined-therapy hearts showed no signs or only minor changes associated with chronic rejection. In conclusion, these results indicate a synergistic effect of combining anti-LFA-1 with CTLA4Ig in inhibiting lymphocyte proliferation and prolonging the survival of fully MHC-mismatched allografts.},
  author       = {Corbascio, Matthias and Ekstrand, Helene and Österholm, Cecilia and Qi, Zhongquan and Simanaitis, Mecislovas and Larsen, Christian P and Pearson, Thomas C and Riesbeck, Kristian and Ekberg, Henrik},
  issn         = {1878-5492},
  language     = {eng},
  number       = {1},
  pages        = {55--61},
  publisher    = {Elsevier},
  series       = {Transplant Immunology},
  title        = {CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.},
  url          = {http://dx.doi.org/10.1016/S0966-3274(02)00014-X},
  volume       = {10},
  year         = {2002},
}