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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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Primed CBY lymphocytes, which reject H2-DMα−/− grafts, do not respond to H2-DMα−/− stimulator cells in a secondary MLR. Total splenocytes from H2-DMα−/− and B6 mice were isolated, irradiated, and combined with spleen cells isolated from recipients of H2-DMα−/− grafts. (A) These cells responded to irradiated stimulator cells from B6 controls (▪), but not H2-DMα−/− animals (□). Data are means ± SD of four animals. (B) The same pattern is observed from naive animals. Mixed lymphocyte reactions were cultured for 5–6 d. Cell proliferation was determined by measuring uptake of [3H]thymidine added 12–18 h before harvest.
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Figure 3: Primed CBY lymphocytes, which reject H2-DMα−/− grafts, do not respond to H2-DMα−/− stimulator cells in a secondary MLR. Total splenocytes from H2-DMα−/− and B6 mice were isolated, irradiated, and combined with spleen cells isolated from recipients of H2-DMα−/− grafts. (A) These cells responded to irradiated stimulator cells from B6 controls (▪), but not H2-DMα−/− animals (□). Data are means ± SD of four animals. (B) The same pattern is observed from naive animals. Mixed lymphocyte reactions were cultured for 5–6 d. Cell proliferation was determined by measuring uptake of [3H]thymidine added 12–18 h before harvest.

Mentions: One possible explanation for the delayed rejection of H2-DMα−/− grafts is that the precursor frequency of CLIP–I-Ab–specific T cells is low in the recipients, and it simply takes longer for these cells to expand and efficiently mediate graft rejection. If this were the case, allogeneic T cells that recognize H2-DMα−/− cells should be expanded after in vivo immunization with the cardiac allograft. To determine if donor-specific T cells had developed in recipients of H2-DMα−/− grafts, an MLR analysis of spleen cells was performed from animals that had received cardiac allografts. The spleens from graft recipients were harvested 7 d after transplant, enriched for T cells, and stimulated with irradiated allogeneic cells. Primed allogeneic T cells from recipients of H2-DMα−/− hearts remained refractory to stimulation by H2-DMα−/− APCs, whereas these same cells responded well to B6 stimulators (Fig. 3 A). The same pattern was observed for T cells from naive animals (Fig. 3 B). Although H2-DMα−/− cells express normal levels of class II, the recipients of H2-DMα−/− hearts failed to develop significant CD4+ T cell reactivity to CLIP– I-Ab complexes.


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)

Primed CBY lymphocytes, which reject H2-DMα−/− grafts, do not respond to H2-DMα−/− stimulator cells in a secondary MLR. Total splenocytes from H2-DMα−/− and B6 mice were isolated, irradiated, and combined with spleen cells isolated from recipients of H2-DMα−/− grafts. (A) These cells responded to irradiated stimulator cells from B6 controls (▪), but not H2-DMα−/− animals (□). Data are means ± SD of four animals. (B) The same pattern is observed from naive animals. Mixed lymphocyte reactions were cultured for 5–6 d. Cell proliferation was determined by measuring uptake of [3H]thymidine added 12–18 h before harvest.
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Related In: Results  -  Collection

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Figure 3: Primed CBY lymphocytes, which reject H2-DMα−/− grafts, do not respond to H2-DMα−/− stimulator cells in a secondary MLR. Total splenocytes from H2-DMα−/− and B6 mice were isolated, irradiated, and combined with spleen cells isolated from recipients of H2-DMα−/− grafts. (A) These cells responded to irradiated stimulator cells from B6 controls (▪), but not H2-DMα−/− animals (□). Data are means ± SD of four animals. (B) The same pattern is observed from naive animals. Mixed lymphocyte reactions were cultured for 5–6 d. Cell proliferation was determined by measuring uptake of [3H]thymidine added 12–18 h before harvest.
Mentions: One possible explanation for the delayed rejection of H2-DMα−/− grafts is that the precursor frequency of CLIP–I-Ab–specific T cells is low in the recipients, and it simply takes longer for these cells to expand and efficiently mediate graft rejection. If this were the case, allogeneic T cells that recognize H2-DMα−/− cells should be expanded after in vivo immunization with the cardiac allograft. To determine if donor-specific T cells had developed in recipients of H2-DMα−/− grafts, an MLR analysis of spleen cells was performed from animals that had received cardiac allografts. The spleens from graft recipients were harvested 7 d after transplant, enriched for T cells, and stimulated with irradiated allogeneic cells. Primed allogeneic T cells from recipients of H2-DMα−/− hearts remained refractory to stimulation by H2-DMα−/− APCs, whereas these same cells responded well to B6 stimulators (Fig. 3 A). The same pattern was observed for T cells from naive animals (Fig. 3 B). Although H2-DMα−/− cells express normal levels of class II, the recipients of H2-DMα−/− hearts failed to develop significant CD4+ T cell reactivity to CLIP– I-Ab complexes.

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