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H2-DMalpha(-/-) mice show the importance of major histocompatibility complex-bound peptide in cardiac allograft rejection.

Felix NJ, Brickey WJ, Griffiths R, Zhang J, Van Kaer L, Coffman T, Ting JP - J. Exp. Med. (2000)

Bottom Line: Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection.Removal of both H2-DMalpha and beta2-microglobulin (beta2m) in cardiac grafts lead to greater (8-10 times) graft survival, whereas removal of beta2m alone did not have any effect.These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

View Article: PubMed Central - PubMed

Affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

ABSTRACT
The role played by antigenic peptides bound to major histocompatibility complex (MHC) molecules is evaluated with H2-DMalpha(-/)- mice. These mice have predominantly class II-associated invariant chain peptide (CLIP)-, not antigenic peptide-bound, MHC class II. H2-DMalpha(-/)- donor heart grafts survived three times longer than wild-type grafts and slightly longer than I-A(beta)(b)-(/)- grafts. Proliferative T cell response was absent, and cytolytic response was reduced against the H2-DMalpha(-/)- grafts in vivo. Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection. Removal of both H2-DMalpha and beta2-microglobulin (beta2m) in cardiac grafts lead to greater (8-10 times) graft survival, whereas removal of beta2m alone did not have any effect. These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

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Related in: MedlinePlus

Graft recipients express both Th1 and Th2 cytokine RNA. Donor hearts were recovered from recipient animals 7 d after transplantation or at the time of graft failure. Total RNA was isolated and analyzed by RNase protection analysis for the presence and level of various cytokine transcripts. No significant difference in the level of any cytokine was observed between groups. The cytokine profile displayed by each recipient group was identical. Data are means ± SD of RNA samples from the indicated number of animals. MIF, macrophage migration inhibitory factor.
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Figure 4: Graft recipients express both Th1 and Th2 cytokine RNA. Donor hearts were recovered from recipient animals 7 d after transplantation or at the time of graft failure. Total RNA was isolated and analyzed by RNase protection analysis for the presence and level of various cytokine transcripts. No significant difference in the level of any cytokine was observed between groups. The cytokine profile displayed by each recipient group was identical. Data are means ± SD of RNA samples from the indicated number of animals. MIF, macrophage migration inhibitory factor.

Mentions: To explore the underlying mechanism for the enhanced survival of H2-DMα−/− grafts, cytokine RNA profile was analyzed by isolating RNA from the donor heart and performing an RNase protection analysis. Those cytokines with detectable levels of RNA are presented in Fig. 4, and all the cytokines tested are listed in Table . Increases in the type 1 cytokine IFN-γ as well as IL-15, IL-6, and IL-10 were observed in all grafted hearts (Fig. 4). H2-DMα−/− donor grafts from two time points were studied: day 7 approximates the time wild-type grafts are typically rejected, and day 20 represents the time when H2-DMα−/− grafts are rejected. However, there were no differences in the level of RNA expression between the different donor groups. There were also increases in the tissue of toxic cytokines TNF-α and lymphotoxin β, but again their levels did not appear to differ between donor groups or to correlate with the rate of rejection. This is not entirely surprising, as enhanced graft survival may not be associated with cytokine expression, although an association between rejection episodes and Th1 cytokine expression is common 4142. Based on the results presented here, the enhanced survival of H2-DMα−/− grafts is not due to a deviation of the immune response to a different cytokine profile.


H2-DMalpha(-/-) mice show the importance of major histocompatibility complex-bound peptide in cardiac allograft rejection.

Felix NJ, Brickey WJ, Griffiths R, Zhang J, Van Kaer L, Coffman T, Ting JP - J. Exp. Med. (2000)

Graft recipients express both Th1 and Th2 cytokine RNA. Donor hearts were recovered from recipient animals 7 d after transplantation or at the time of graft failure. Total RNA was isolated and analyzed by RNase protection analysis for the presence and level of various cytokine transcripts. No significant difference in the level of any cytokine was observed between groups. The cytokine profile displayed by each recipient group was identical. Data are means ± SD of RNA samples from the indicated number of animals. MIF, macrophage migration inhibitory factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887714&req=5

Figure 4: Graft recipients express both Th1 and Th2 cytokine RNA. Donor hearts were recovered from recipient animals 7 d after transplantation or at the time of graft failure. Total RNA was isolated and analyzed by RNase protection analysis for the presence and level of various cytokine transcripts. No significant difference in the level of any cytokine was observed between groups. The cytokine profile displayed by each recipient group was identical. Data are means ± SD of RNA samples from the indicated number of animals. MIF, macrophage migration inhibitory factor.
Mentions: To explore the underlying mechanism for the enhanced survival of H2-DMα−/− grafts, cytokine RNA profile was analyzed by isolating RNA from the donor heart and performing an RNase protection analysis. Those cytokines with detectable levels of RNA are presented in Fig. 4, and all the cytokines tested are listed in Table . Increases in the type 1 cytokine IFN-γ as well as IL-15, IL-6, and IL-10 were observed in all grafted hearts (Fig. 4). H2-DMα−/− donor grafts from two time points were studied: day 7 approximates the time wild-type grafts are typically rejected, and day 20 represents the time when H2-DMα−/− grafts are rejected. However, there were no differences in the level of RNA expression between the different donor groups. There were also increases in the tissue of toxic cytokines TNF-α and lymphotoxin β, but again their levels did not appear to differ between donor groups or to correlate with the rate of rejection. This is not entirely surprising, as enhanced graft survival may not be associated with cytokine expression, although an association between rejection episodes and Th1 cytokine expression is common 4142. Based on the results presented here, the enhanced survival of H2-DMα−/− grafts is not due to a deviation of the immune response to a different cytokine profile.

Bottom Line: Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection.Removal of both H2-DMalpha and beta2-microglobulin (beta2m) in cardiac grafts lead to greater (8-10 times) graft survival, whereas removal of beta2m alone did not have any effect.These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

View Article: PubMed Central - PubMed

Affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

ABSTRACT
The role played by antigenic peptides bound to major histocompatibility complex (MHC) molecules is evaluated with H2-DMalpha(-/)- mice. These mice have predominantly class II-associated invariant chain peptide (CLIP)-, not antigenic peptide-bound, MHC class II. H2-DMalpha(-/)- donor heart grafts survived three times longer than wild-type grafts and slightly longer than I-A(beta)(b)-(/)- grafts. Proliferative T cell response was absent, and cytolytic response was reduced against the H2-DMalpha(-/)- grafts in vivo. Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection. Removal of both H2-DMalpha and beta2-microglobulin (beta2m) in cardiac grafts lead to greater (8-10 times) graft survival, whereas removal of beta2m alone did not have any effect. These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

Show MeSH
Related in: MedlinePlus