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Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L.

Kumagai-Braesch, Makiko; Ekberg, Henrik LU ; Wang, Feng; Osterholm, Cecilia; Ehrnfelt, Cecilia; Sharma, Amit; Lindeborg, Ellinor; Holgersson, Jan and Corbascio, Matthias (2007) In Transplantation 83(9). p.1259-1267
Abstract
Background. It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C5713L/6 mice with streptozotocin-induced diabetes. Methods. Recipients were treated with CTLA4Ig/anti-CD40L +/- anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months. Results. Recipients treated with... (More)
Background. It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C5713L/6 mice with streptozotocin-induced diabetes. Methods. Recipients were treated with CTLA4Ig/anti-CD40L +/- anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months. Results. Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L +/- anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens. Conclusions. CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CTLA4Ig, anti-CD40L, anti-LFA-1, pig islet transplantation, costimulatory blockade
in
Transplantation
volume
83
issue
9
pages
1259 - 1267
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000246668500019
  • scopus:34248332137
ISSN
1534-6080
DOI
10.1097/01.tp.0000261722.02697.75
language
English
LU publication?
yes
id
c878ca45-3c35-4ba8-9246-80e63dbdb637 (old id 168328)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17496544&dopt=Abstract
date added to LUP
2007-07-24 16:23:49
date last changed
2017-09-24 04:33:41
@article{c878ca45-3c35-4ba8-9246-80e63dbdb637,
  abstract     = {Background. It has been previously demonstrated that addition of anti-LFA-1 to a combination of CTLA4Ig and anti-CD40L induces the permanent acceptance of dopaminergic fetal pig xenografts when transplanted into the brain of wild-type mice. The purpose of this study was to test whether this costimulation blockade also can induce acceptance of adult pig islets transplanted to C5713L/6 mice with streptozotocin-induced diabetes. Methods. Recipients were treated with CTLA4Ig/anti-CD40L +/- anti-LFA-1 or isotype control antibodies during the first week after transplantation. Half of the costimulation blockade-treated recipients had their grafts removed after 8 weeks. The other half was observed up to 5 months. Results. Recipients treated with CTLA4Ig/anti-CD40L/anti-LFA-1 had significantly lower blood glucose and gained more weight than CTLA4Ig/anti-CD40L-treated recipients. CTLA4Ig/anti-CD40L-treated recipients exhibited unstable blood glucose. IPGTT of these recipients revealed a slow recovery to normal blood glucose levels at week 4. In comparison, CTLA4Ig/anti-CD40L/anti-LFA-1 treated recipients exhibited a significantly superior glucose clearance. CTLA4Ig/anti-CD40L +/- anti-LFA-1 treated recipients did not produce anti-pig IgG, whereas control antibody-treated mice did. CD4+ T cells from costimulation blockade-treated recipients proliferated less than CD4+ T cells from control antibody-treated mice when co-cultured with syngeneic antigen presenting cells loaded with pig islet antigens. Conclusions. CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.},
  author       = {Kumagai-Braesch, Makiko and Ekberg, Henrik and Wang, Feng and Osterholm, Cecilia and Ehrnfelt, Cecilia and Sharma, Amit and Lindeborg, Ellinor and Holgersson, Jan and Corbascio, Matthias},
  issn         = {1534-6080},
  keyword      = {CTLA4Ig,anti-CD40L,anti-LFA-1,pig islet transplantation,costimulatory blockade},
  language     = {eng},
  number       = {9},
  pages        = {1259--1267},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Transplantation},
  title        = {Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L.},
  url          = {http://dx.doi.org/10.1097/01.tp.0000261722.02697.75},
  volume       = {83},
  year         = {2007},
}