Murine liver allograft transplantation: Tolerance and donor cell chimerism

Nonarterialized orthotopic liver transplantation with no immunosuppression was performed in 13 mouse‐strain combinations. Two strain combinations with major histocompatibility complex class I and class II and minor histocompatibility complex disparity had 20% and 33% survival of more than 100 days, but the other 11 combinations, including four that were fully allogeneic and all with only class I, class II or minor disparities, yielded 45% to 100% survival of more than 100 days. Long‐living recipients permanently accepted donor‐strain heterotopic hearts transplanted on the same day or donor‐strain skin 3 mo after liver transplantation, in spite of detectable antidonor in vitro activity with mixed lymphocyte reaction and cellmediated lymphocytotoxicity testing (split tolerance). In further donor‐specific experiments, liver grafts were not rejected by presensitized major histocompatibility complex class I‐disparate recipients and they protected donor‐strain skin grafts from second set (or any) rejection. Less frequently, liver transplantation rescued rejecting skin grafts placed 1 wk earlier in major histocompatibility complex class I, class II and minor histocompatibility complex, class II or minor histocompatibility complex‐disparate strain combinations. Donor‐derived leukocyte migration to the central lymphoid organs occurred within 1 to 2 hr after liver transplantation in all animals examined, persisted in the surviving animals until they were killed (>375 days), and was demonstrated with double‐immunolabeling to be multilineage. The relation of these findings to so‐called hepatic tolerogenicity and to tolerance in general is discussed. (HEPATOLOGY 1994;19:916–924.) Copyright © 1994 American Association for the Study of Liver Disease

Major Histocompatibility Complex and Cell Cooperation

We have studied the role of major histocompatibility antigens on cell cooperation in the immune response of the chicken. In the 1970's, shortly after the initial discoveries in the mouse, we demonstrated that the T cell-B cell interaction is major histocompatibility complex (MHC)-dependent in the chicken and requires at least one haplotype identity between the collaborating cells. Later, by using MHC-congenic and MHC-recombinant lines, we demonstrated that the T-B cell interaction in antibody response is MHC-restricted, and more precisely, Class II MHC-antigen-restricted. Furthermore, we proved that T-B cell cooperation in splenic germinal center formation is likewise class II MHC antigen-restricted. Recently, we have focused our studies on MHC antigen identity requirements during antigen presentation by macrophages to T cells. In these studies, Class II antigens were found to serve as restriction elements in antigen recognition by T cells. Cytotoxic T cells of the chicken have been shown to be MHC-restricted in their function. Whether Class I or Class II MHC antigens serve as restriction molecules has not yet been determined. In conclusion, it is obvious that the function of the avian immune response is controlled by the polymorphic MHC gene products in the same way as that in the mammalian specie

Cryptic female choice favours sperm from major histocompatibility complex-dissimilar males

Cryptic female choice may enable polyandrous females to avoid inbreeding or bias offspring variability at key loci after mating. However, the role of these genetic benefits in cryptic female choice remains poorly understood. Female red junglefowl, Gallus gallus, bias sperm use in favour of unrelated males. Here, we experimentally investigate whether this bias is driven by relatedness per se, or by similarity at the major histocompatibility complex (MHC), genes central to vertebrate acquired immunity, where polymorphism is critical to an individual's ability to combat pathogens. Through experimentally controlled natural matings, we confirm that selection against related males' sperm occurs within the female reproductive tract but demonstrate that this is more accurately predicted by MHC similarity: controlling for relatedness per se, more sperm reached the eggs when partners were MHC-dissimilar. Importantly, this effect appeared largely owing to similarity at a single MHC locus (class I minor). Further, the effect of MHC similarity was lost following artificial insemination, suggesting that male phenotypic cues might be required for females to select sperm differentially. These results indicate that postmating mechanisms that reduce inbreeding may do so as a consequence of more specific strategies of cryptic female choice promoting MHC diversity in offspring

Downregulation of major histocompatibility complex class I in bovine papillomas

Bovine papillomavirus (BPV) induces papillomas in cattle; in the great majority of cases, these regress due to the host immune response, but they can persist and progress to malignancy. Even in the absence of malignant transformation, BPV infection persists for a significant period of time before activation of the host immune system, suggesting that the host immune system is unaware of, or disabled by, BPV. E5 is the major oncoprotein of BPV, which, in addition to its transforming properties, downregulates the expression and transport to the cell surface of major histocompatibility complex class I (MHC I). Here, it is shown that co-expression of MHC I and E5 in papillomas caused by BPV-4 infection is mutually exclusive, in agreement with the inhibition of surface MHC I expression by E5 that is observed in vitro. The inhibition of MHC expression in E5-expressing papilloma cells could explain the long period that is required for activation of the immune response and has implications for the progression of papillomas to the malignant stage; absence of peptide presentation by MHC I to cytotoxic T lymphocytes would allow the infected cells to evade the host cellular immune response and allow the lesions to persist

A Nonpolymorphic Class I Gene in the Murine Major Histocompatibility Complex

DNA sequence analysis of a class I gene (QlO), which maps to the Qa2,3 locus in the C57BL/lO (H- 2b haplotype) mouse, reveals that it is almost identical to a cDNA clone (pH16) isolated from a SWR/J (H-2q haplotype) mouse liver cDNA library. Exon 5, in particular, has an unusual structure such that a polypeptide product is unlikely to be anchored in the cell membrane. Our findings suggest that the two sequences are derived from allelic class I genes, which are nonpolymorphic, in contrast to H-2K allelic sequences from the same mice, and they may encode liver-specific polypeptides of unknown function. Our previous studies indicate that the QlO gene is a potential donor gene for the generation of mutations at the H-2K locus by inter-gene transfer of genetic information. Thus the lack of polymorphism in class I genes at the QlO locus implies either that they are not recipients for such exchanges or that selective pressure prevents the accumulation of mutations in genes at this locus

Minors come of age: minor histocompatibility antigens and graft-versus-host disease

AbstractMinor histocompatibility antigens (miHA) are responsible for the occurrence of graft-versus-host disease in the setting of a major histocompatibility complex matched sibling allogeneic stem cell transplantation. These miHA are peptide fragments that are associated with major histocompatibility complex class I or class II antigens. Elegant experiments have led to the molecular characterization of these antigens. Efforts to prevent graft-versus-host disease could be targeted through this pathway by matching for these miHA or by preventing antigen recognition. Alternatively, these miHA could be exploited as targets for a more potent graft-versus-malignancy effect. This area of miHA promises to continue to be an exciting area of continued research

A natural killer cell receptor specific for a major histocompatibility complex class I molecule.

Target cell expression of major histocompatibility complex (MHC) class I molecules correlates with resistance to lysis by natural killer (NK) cells. Prior functional studies of the murine NK cell surface molecule, Ly-49, suggested its role in downregulating NK cell cytotoxicity by specifically interacting with target cell H-2Dd molecules. In support of this hypothesis, we now demonstrate a physical interaction between H-2Dd and Ly-49 in both qualitative and quantitative cell-cell binding assays employing a stable transfected Chinese hamster ovary (CHO) cell line expressing Ly-49 and MHC class I transfected target cells. Binding occurred only when CHO cells expressed Ly-49 at high levels and targets expressed H-2Dd by transfection. Monoclonal antibody blocking experiments confirmed this interaction. These studies indicate that the specificity of natural killing is influenced by NK cell receptors that engage target cell MHC class I molecules

Determination of a predictive cleavage motif for eluted major histocompatibility complex class II ligands

CD4+ T cells have a major role in regulating immune responses. They are activated by recognition of peptides mostly generated from exogenous antigens through the major histocompatibility complex (MHC) class II pathway. Identification of epitopes is important and computational prediction of epitopes is used widely to save time and resources. Although there are algorithms to predict binding affinity of peptides to MHC II molecules, no accurate methods exist to predict which ligands are generated as a result of natural antigen processing. We utilized a dataset of around 14,000 naturally processed ligands identified by mass spectrometry of peptides eluted from MHC class II expressing cells to investigate the existence of sequence signatures potentially related to the cleavage mechanisms that liberate the presented peptides from their source antigens. This analysis revealed preferred amino acids surrounding both N- and C-terminuses of ligands, indicating sequence-specific cleavage preferences. We used these cleavage motifs to develop a method for predicting naturally processed MHC II ligands, and validated that it had predictive power to identify ligands from independent studies. We further confirmed that prediction of ligands based on cleavage motifs could be combined with predictions of MHC binding, and that the combined prediction had superior performance. However, when attempting to predict CD4+ T cell epitopes, either alone or in combination with MHC binding predictions, predictions based on the cleavage motifs did not show predictive power. Given that peptides identified as epitopes based on CD4+ T cell reactivity typically do not have well-defined termini, it is possible that motifs are present but outside of the mapped epitope. Our attempts to take that into account computationally did not show any sign of an increased presence of cleavage motifs around well-characterized CD4+ T cell epitopes. While it is possible that our attempts to translate the cleavage motifs in MHC II ligand elution data into T cell epitope predictions were suboptimal, other possible explanations are that the cleavage signal is too diluted to be detected, or that elution data are enriched for ligands generated through an antigen processing and presentation pathway that is less frequently utilized for T cell epitopes.Fil: Paul, Sinu. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Karosiene, Edita. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Dhanda, Sandeep Kumar. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Jurtz, Vanessa. Technical University of Denmark; DinamarcaFil: Edwards, Lindy. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Sette, Alessandro. University of California at San Diego; Estados Unidos. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados Unidos. University of California at San Diego; Estados Unido

Lack of class I H-2 antigens in cells transformed by radiation leukemia virus is associated with methylation and rearrangement of H-2 DNA

Transformation of murine thymocytes by radiation leukemia virus is associated with reduced expression of the class I antigens encoded in the major histocompatibility complex (MHC) and increased methylation and altered restriction enzyme patterns of MHC DNA. These changes may play a role in host susceptibility to virus-induced leukemogenesis and accord with the notion that viral genomes play a regulatory function when they integrate adjacent to histocompatibiity genes