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Effects of Lipopolysaccharide on the Induction of Mixed Chimerism in Cyclophosphamide‐Induced Tolerance
Author(s) -
Onzuka T.,
Tomita Y.,
Shimizu I.,
Okano S.,
Yamada H.,
Yoshikai Y.,
Tominaga R.
Publication year - 2009
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2009.02314.x
Subject(s) - cyclophosphamide , lipopolysaccharide , immune tolerance , tlr4 , immunology , immune system , spleen , medicine , pharmacology , chemotherapy
Cyclophosphamide (CP)‐induced tolerance is a mixed chimerism‐based tolerance and is one of the strategies used to induce transplant tolerance. Toll‐like receptor (TLR) agonists are reportedly able to abrogate the induction of tolerance by activating alloreactive T cells, or by inhibiting Treg cells. However, little is known about the effect of the immune response mediated by TLR on mixed chimerism‐based tolerance protocols. In this study, we evaluated the influence of lipopolysaccharide (LPS), which is best known as an TLR4 agonist, on CP‐induced tolerance. BALB/c (H‐2 d ) mice received a conditioning regimen consisting of 10 8 donor DBA/2 (H‐2 d ) spleen cells (SC) on day 0 and 200 mg/kg CP on day 2. A single dose of 20 μg LPS was injected on day −2, 0, 7, or 35. Our results showed that LPS infusion at any time point resulted in chronic rejection of donor skin grafts and the abrogation of mixed chimerism in 33–60% of recipients. We found a correlation between skin graft acceptance and higher levels of mixed chimerism. Flow cytometric analysis revealed that donor‐reactive T cells were permanently eliminated, regardless of LPS infusion. In conclusion, LPS‐infusion had little influence on the immune response of donor‐reactive T cells, but had a significant effect on the induction and maintenance of mixed chimerism in CP‐induced tolerance.