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Induction of operational tolerance to allografts and xenografts

Corbascio, Matthias LU (2002)
Abstract (Swedish)
Popular Abstract in Swedish

Med dagens medicinska teknik måste mottagare av transplanterade organ ta immundämpande läkemedel varje dag för att undvika att transplantatet avstöts. Dessa patienter får ett generellt nedsatt immunförsvar vilket betyder att de blir mottagliga för infektionssjukdomar, samt har en ökad risk för att utveckla tumörer. När det gäller transplantation av vävnader från andra arter, så kallad xenotransplantation, är avstötningsreaktionen såpass aggressiv att immunosuppression med dagens läkemedel ej är tillräcklig.



För att lösa dessa problem har man under senare år börjat utveckla en strategi som går ut på att blockera signaler mellan de immunförsvarsceller som är viktiga för... (More)
Popular Abstract in Swedish

Med dagens medicinska teknik måste mottagare av transplanterade organ ta immundämpande läkemedel varje dag för att undvika att transplantatet avstöts. Dessa patienter får ett generellt nedsatt immunförsvar vilket betyder att de blir mottagliga för infektionssjukdomar, samt har en ökad risk för att utveckla tumörer. När det gäller transplantation av vävnader från andra arter, så kallad xenotransplantation, är avstötningsreaktionen såpass aggressiv att immunosuppression med dagens läkemedel ej är tillräcklig.



För att lösa dessa problem har man under senare år börjat utveckla en strategi som går ut på att blockera signaler mellan de immunförsvarsceller som är viktiga för aktivering av T-celler. Det är T-cellerna som huvudsakligen anses mediera avstötning av ett transplantat. Två molekyler, B7 och CD40L har visat sig vara mycket viktiga vid T-cellsaktivering. Blockering av B7 och CD40L har fungerat väl vid experimentell transplantation i en särskild stam av möss (C3H) men har däremot inte haft någon effekt i en annan stam (C57BL/6). Det har visat sig att de sistnämnda mössen har T-celler som kan aktiveras utan signalering genom B7 och CD40L.



I detta arbete har strategin varit att kombinera blockering av B7 och CD40L med en antikropp som riktar sig mot en tredje molekyl, LFA-1. Även denna molekyl är känd för att vara viktig vid aktivering av CD8+ T-celler. Vi har använt trippelblockad vid hjärttransplantation mellan möss (där mottagarstammen är C57BL/6) samt vid transplantation av hjärnceller (neuron) från gris till mus. Behandlingen har getts under en veckas tid från transplantationstillfället (s.k. induktionsbehandling). Resultatet är långsiktig överlevnad av hjärttransplantat och neuron från grisar. Vi har sedan visat att detta uppnås genom uppkomsten av regulatoriska T-celler, vilka hindrar värdens T-celler från att avstöta organet och istället behandlar det som om det vore kroppens eget. Dessa resultat kan bli en del i en utveckling där patienter som har blivit organtransplanterade slipper ta immundämpande medel och att patienter med Parkinson’s sjukdom och andra neurologiska sjukdomar kan få behandling med celler från grisfoster. (Less)
Abstract
Inhibition of the costimulatory molecules B7 and CD40L with CTLA4Ig and anti-CD40L administered only during the first week after transplantation induces indefinite survival of allo- and xenogeneic heart transplants and significantly prolongs skin grafts in C3H mice. However, this treatment protocol is not as effective in C57BL/6 mice which reject skin transplants with nearly the same median survival time as untreated controls. This has been shown to be due to the ability of CD8+ T cells to be activated autonomously of B7 or CD40L costimulation. LFA-1 is an important signaling molecule for CD8+ T cell function and we therefore hypothesized that its inhibition may compliment B7 and CD40L blockade and induce indefinite survival of transplants... (More)
Inhibition of the costimulatory molecules B7 and CD40L with CTLA4Ig and anti-CD40L administered only during the first week after transplantation induces indefinite survival of allo- and xenogeneic heart transplants and significantly prolongs skin grafts in C3H mice. However, this treatment protocol is not as effective in C57BL/6 mice which reject skin transplants with nearly the same median survival time as untreated controls. This has been shown to be due to the ability of CD8+ T cells to be activated autonomously of B7 or CD40L costimulation. LFA-1 is an important signaling molecule for CD8+ T cell function and we therefore hypothesized that its inhibition may compliment B7 and CD40L blockade and induce indefinite survival of transplants in mice.



Anti-LFA-1 combined with CTLA4Ig induced indefinite survival of heart transplants after one week of treatment. Anti-LFA-1 also prevented immune responses and chronic vasculopathy in CD40L -/- mice. When CTLA4Ig was combined with anti-LFA-1 and given to CD40L -/- mice, dopaminergic porcine xenografts were accepted without any signs of rejection. The combination of anti-CD40L, CTLA4Ig and anti-LFA-1 induced permanent acceptance of dopaminergic porcine grafts in wild-type C57BL/6 mice. Surprisingly these recipients could be induced to rejected their grafts if challenged with glia cells of donor origin indicating that regulatory T cells maybe involved in the acceptance of these transplants. In order to ascertain the importance of regulatory T cells, IL-10 deficient mice were transplanted with allogeneic heart transplants and treated with costimulation blockade. A majority of these hearts stopped beating two days after transplantation succumbing to a massive neutrophilic infiltrate resembling myocardial infarction. The remaining hearts were rejected with in 50 days after transplantation. These results indicate that anti-LFA-1 can compliment CTLA4Ig and anti-CD40L in the induction of operational tolerance and that this state is facilitated by IL-10 and indirectly regulatory T cells. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof Wood, Kathryn, University of Oxford, Nuffield Department of Surgery
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, Immunologi, serologi, serology, Immunology, allograft, xenograft, heart transplantation, tolerance, anti-LFA-1, CTLA4Ig, anti-CD40L
pages
47 pages
publisher
Matthias Corbascio,
defense location
Kirurgens föreläsningssal kl 9.15, 25 november 2002
defense date
2002-11-25 09:15
ISBN
91-628-5444-5
language
English
LU publication?
yes
id
315c1f31-45a5-4233-bc45-e1414807bb2c (old id 465191)
date added to LUP
2007-09-10 15:27:55
date last changed
2016-09-19 08:45:08
@phdthesis{315c1f31-45a5-4233-bc45-e1414807bb2c,
  abstract     = {Inhibition of the costimulatory molecules B7 and CD40L with CTLA4Ig and anti-CD40L administered only during the first week after transplantation induces indefinite survival of allo- and xenogeneic heart transplants and significantly prolongs skin grafts in C3H mice. However, this treatment protocol is not as effective in C57BL/6 mice which reject skin transplants with nearly the same median survival time as untreated controls. This has been shown to be due to the ability of CD8+ T cells to be activated autonomously of B7 or CD40L costimulation. LFA-1 is an important signaling molecule for CD8+ T cell function and we therefore hypothesized that its inhibition may compliment B7 and CD40L blockade and induce indefinite survival of transplants in mice.<br/><br>
<br/><br>
Anti-LFA-1 combined with CTLA4Ig induced indefinite survival of heart transplants after one week of treatment. Anti-LFA-1 also prevented immune responses and chronic vasculopathy in CD40L -/- mice. When CTLA4Ig was combined with anti-LFA-1 and given to CD40L -/- mice, dopaminergic porcine xenografts were accepted without any signs of rejection. The combination of anti-CD40L, CTLA4Ig and anti-LFA-1 induced permanent acceptance of dopaminergic porcine grafts in wild-type C57BL/6 mice. Surprisingly these recipients could be induced to rejected their grafts if challenged with glia cells of donor origin indicating that regulatory T cells maybe involved in the acceptance of these transplants. In order to ascertain the importance of regulatory T cells, IL-10 deficient mice were transplanted with allogeneic heart transplants and treated with costimulation blockade. A majority of these hearts stopped beating two days after transplantation succumbing to a massive neutrophilic infiltrate resembling myocardial infarction. The remaining hearts were rejected with in 50 days after transplantation. These results indicate that anti-LFA-1 can compliment CTLA4Ig and anti-CD40L in the induction of operational tolerance and that this state is facilitated by IL-10 and indirectly regulatory T cells.},
  author       = {Corbascio, Matthias},
  isbn         = {91-628-5444-5},
  keyword      = {transplantation,Immunologi,serologi,serology,Immunology,allograft,xenograft,heart transplantation,tolerance,anti-LFA-1,CTLA4Ig,anti-CD40L},
  language     = {eng},
  pages        = {47},
  publisher    = {Matthias Corbascio,},
  school       = {Lund University},
  title        = {Induction of operational tolerance to allografts and xenografts},
  year         = {2002},
}