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PubMed1985

MHC and non-MHC genetic influences on Rous sarcoma metastasis in chickens.

The B5/B5 genotype, in Leghorns, was associated with a high degree of metastasis of Rous sarcoma virus-induced tumors, but in combination with a Leghorn-New Hampshire background markedly less metastasis occurred. Initially, four mating types were used: B5/B5 X B5/B5 chickens from the F5 generation of the cross of Leghorn lines 6(1) and 15(1), B24/B24 X B24/B24 chickens from line UNH 105 (New Hampshires), and reciprocal crosses of B5/B5 X B24/B24 chickens. Subsequently, F2 generation progeny of the cross of B5/B5 and B24/B24 breeders, as well as B24/B24 line UNH 105 and B5/B5 (6(1) X 15(1))F2 chickens, were used. Six-week-old chickens were inoculated in the wingweb with Rous sarcoma virus. Chickens dying during a 10-week period after inoculation were necropsied and suspect metastatic lesions examined histologically. Among 234 terminal chickens from the initial four mating types the incidence of metastasis associated with B5/B5 Leghorns (66%) was substantially higher than for B24/B24 New Hampshires (12%) and B5/B24 progeny of reciprocal Leghorn-New Hampshire crosses (19 and 24%). Subsequently, among 524 terminal hosts in the Leghorn-New Hampshire F2 population, B genotype significantly influenced tumor dissemination. However, among 52 concurrently challenged B5/B5 hosts from the (6(1) X 15(1))F2 population the incidence of metastasis (60%) was significantly higher than among 122 B5/B5 hosts from the Leghorn-New Hampshire F2 population (31%), indicating a non-major histocompatibility complex genetic effect on metastasis.

Animals↗
PubMed1997

Cellular and molecular analyses of major histocompatibility complex (MHC) restricted and non-MHC-restricted effector cells recognizing renal cell carcinomas: problems and perspectives for immunotherapy.

Renal cell carcinomas belong to the small group of tumors that are able to induce antitumor responses. Here we describe two general types of cytotoxic effector lymphocytes that can eliminate autologous tumor cells and discuss the role that major histocompatibility complex encoded molecules play in governing their specificities. Improved understanding of the cellular and molecular basis of renal cell carcinoma recognition opens new avenues of research with the potential to develop better immunotherapies for patients with metastatic disease.

Antigen-Antibody Reactions↗
PubMed1995

The cytoplasmic and transmembrane domains of MHC class II beta chains deliver distinct signals required for MHC class II-mediated B cell activation.

Class II-mediated signals play potential roles in B cell activation and antigen presentation. The regions of the class II molecule participating in B cell signaling are incompletely defined. Our prior analysis of structural requirements of the cytoplasmic domain of A beta revealed that only the eight membrane-proximal residues are required for signaling. Here, we report that the sequence and position of two of these are critical, and present direct evidence that the A beta transmembrane domain is also involved in signaling, via a pathway distinct from the cytoplasmic domain. These results demonstrate that specific regions in both the cytoplasmic and transmembrane domains of the class II molecule have distinct signaling functions.

Amino Acid Sequence↗
PubMed1983

Spontaneous diabetes mellitus syndrome in the rat. IV. Immunogenetic interactions of MHC and non-MHC components of the syndrome.

We have examined the frequency of three phenotypic characteristics of the syndrome of spontaneous diabetes (overt IDDM, lymphocytic infiltration of the pancreas, and depression of T lymphocytes) in the offspring of crosses between IDDM BB rats and rats of strains with the same and different RT1 genotypes. On the basis of these observations we propose that there are at least three components of the diabetic syndrome in the rat: (1) a requirement for the RT1u haplotype from the BB strain or a gene in close linkage with the gene coding for this haplotype, (2) a susceptibility for development of insular, periductular, or intraacinar lymphocytic infiltration in the pancreas, and (3) a susceptibility to depression of T lymphocytes. Interactions between these components as well as with other genetic and environmental factors contribute to the full expression of the syndrome.

Animals↗
PubMed1998

MHC class I heavy chain mRNA must exceed a threshold level for the reconstitution of cell surface expression of class I MHC complexes in cells transformed by the highly oncogenic adenovirus 12.

In primary embryonal fibroblasts from transgenic mice expressing H-2(b) genes and a miniature swine class I transgene (PD1), transformation with adenovirus 12 results in suppression of assembly and cell surface expression of all class I complexes. Cell surface expression of PD1 can be recovered by transfecting the cells with peptide transporter genes. However, reconstitution of the H-2Kb gene expression requires, in addition, a 2-fold increase in the steady state level of the H-2Kb mRNA that can be attained by treatment of the cells with interferons or by transfecting them with the H-2Kb gene. A detailed analyses of the biogenesis of class I molecules has revealed the steady state expression of free class I heavy chains that are not converted into conformed complexes even when peptide transporter genes are overexpressed. The fact that class I complex assembly seems to be highly inefficient in certain cell lines might be a major in vivo obstacle for the elimination of transformed or virus-infected cells by cytotoxic T lymphocytes, especially in view of the fact that the level of class I gene transcription is often down-regulated in cancer cells and/or that assembly of class I major histocompatibility complexes can be subverted by virus-encoded proteins.

Adenoviridae↗
PubMed1993

Changes at peptide residues buried in the major histocompatibility complex (MHC) class I binding cleft influence T cell recognition: a possible role for indirect conformational alterations in the MHC class I or bound peptide in determining T cell recognition.

Recent crystallographic studies on two peptide complexes with the mouse Kb molecule have shown that peptide binding appears to alter the conformation of the class I alpha-helical regions that flank the antigen binding cleft. Given that this study also showed that much of the foreign peptide is buried within the class I binding cleft with only a small portion accessible for direct interaction with the components of the T cell receptor, this finding suggests that at least some component of T cell specificity may arise as a consequence of peptide-induced conformational changes in the class I structure. To assess this possibility, we have made systematic substitutions at residues within the Kb-restricted determinant from ovalbumin (OVA257-264) that are thought to be buried on binding to the class I molecule. We have found that changes in this determinant at the completely buried second residue (P2) can influence T cell recognition without affecting binding to Kb, suggesting that the substitutions may indirectly determine T cell recognition by altering the conformation of the class I molecule or the bound peptide.

Amino Acids↗
PubMed1993

Presentation of numerous viral peptides to mouse major histocompatibility complex (MHC) class I-restricted T lymphocytes is mediated by the human MHC-encoded transporter or by a hybrid mouse-human transporter.

The major histocompatibility complex-encoded transporter associated with antigen processing (TAP) is required for the efficient presentation of cytosolic antigens to class I-restricted T cells. TAP is thought to be formed by the interaction of two gene products, termed TAP1 and TAP2. We find that TAPs consisting either of human subunits, or mouse TAP1 and human TAP2, facilitate the presentation of numerous defined viral peptides to mouse class I-restricted T cells. As human and mouse TAP2 and TAP1 differ in 23 and 28% of their residues, respectively, this indicates that TAP1 and TAP2 can form a functional complex with partners considerably different from those they coevolved with. Moreover, these findings indicate that widely disparate TAPs facilitate delivery of the same peptides to class I molecules. These findings suggest that TAP polymorphism does not greatly influence the types of peptides presented to the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability.

DM edits the peptide repertoire presented by major histocompatibility complex class II molecules by professional antigen-presenting cells (APCs), favoring presentation of some peptides over others. Despite considerable research by many laboratories, there is still significant uncertainty regarding the biochemical attributes of class II-peptide complexes that govern their susceptibility to DM editing. Here, using APCs that either do or do not express DM and a set of unrelated antigens, we found that the intrinsic kinetic stability of class II-peptide complexes is tightly correlated with the effects of DM editing within APCs. Furthermore, through the use of kinetic stability variants of three independent peptides, we demonstrate that increasing or decreasing the kinetic stability of class II-peptide complexes causes a corresponding alteration in DM editing. Finally, we show that the spontaneous kinetic stability of class II complexes correlates directly with the efficiency of presentation by DM+ APCs and the immunodominance of that class II-peptide complex during an immune response. Collectively, these results suggest that the pattern of DM editing in APCs can be intentionally changed by modifying class II-peptide interactions, leading to the desired hierarchy of presentation on APCs, thereby promoting recruitment of CD4 T cells specific for the preferred peptides during an immune response.

Animals↗
PubMed1999

Targeting of hepatitis C virus core protein for MHC I or MHC II presentation does not enhance induction of immune responses to DNA vaccination.

We analyzed different vaccine approaches aimed at enhancing CD4(+)- and CD8(+)-dependent responses against hepatitis C virus (HCV) core antigen. Specific DNA vectors expressing various forms of the core in fusion with the ubiquitin or the lysosome-associated membrane protein (LAMP) were generated. These expressed the full-length wildtype core; the full-length core expressed as a covalent fusion with the ubiquitin; the full-length core expressed as a noncovalent fusion with the ubiquitin and containing a N-stabilizing or N-destabilizing residue; and the full-length core expressed as a fusion with the LAMP sequence. In vitro expression levels of the different plasmids differed by as much as tenfold. After injection into mice, none of the plasmids yielded a detectable antibody response, whereas core-specific cytotoxic T-lymphocyte (CTL) activity could be observed with all plasmids as long as 21 weeks postimmunization. No increase in CTL activity (ranging from 7% to 34% specific lysis) was observed with the ubiquitin-fusion-expressed core antigens compared with the wildtype core. The lowest CTL activity (< 5% specific lysis) was observed with the LAMP fusion. This vector was nonetheless unable to induce a detectable proliferative response. Screening of 10 different putative CTL peptide epitopes failed to reveal newly targeted epitopes when the core-fusion plasmids were used compared with the wildtype core-expressing plasmid. These data underline the difficulty in optimizing anti-core cellular immune response using molecular targeting strategies in DNA-based vaccination.

Animals↗
PubMed1995

Transduction of genes coding for a histocompatibility (MHC) antigen and for its physiological inducer interferon-gamma in the same cell: efficient MHC expression and inhibition of tumor and metastasis growth.

The mouse mammary carcinoma TS/A, of BALB/c (H-2d) origin, was transfected with the murine interferon-gamma (IFN-gamma) gene (Int. J. Cancer 55: 320, 1993). We used IFN-gamma transfectants as recipients for a second round of transfections with murine allogeneic class I histocompatibility (H-2b) genes that are modulated by IFN. Transfectants with either gene alone, as well as parent TS/A cells (TS/A-pc), were used as controls. Only double transfectants expressed high levels of the allogeneic H-2b genes, while in H-2b single transfectants the expression was very low (but was induced by treatment with exogenous IFN-gamma). The tumorigenic potential of IFN-gamma or H-2b single transfectants was reduced in comparison to TS/A-pc. IFN-gamma+H-2Kb double transfectants were almost nontumorigenic, while IFN-gamma+H-2Db clones gave rise to tumors in about one-half of mice. The experimental metastatic ability of all IFN-gamma+H-2b double transfectants was very low. IFN-gamma single transfectants were known to induce a strong macrophage response in the host. The expression of allogeneic H-2 antigens added a T-lymphocyte-mediated response that accounted for the lower tumorigenicity of double transfectants. These results show that it is possible to steer the immune response evoked by tumor cells for therapeutic purposes. Moreover, the high H-2 expression obtained in IFN-gamma+H-2b double transfectants suggests that single IFN-gamma transfectants are ideal recipients for all IFN-sensitive genes. This approach can be used also for other general-purpose inducers of gene expression.

Animals↗
PubMed1992

Evidence that rapamycin rescue therapy delays rejection of major (MHC) plus minor (non-MHC) histoincompatible heart allografts in rats.

The capacity of delayed onset of rapamycin (RAPA) therapy to block process of destruction was examined in rats undergoing heart allograft rejection. Untreated Wistar Furth (WFu; RT-1u) recipients reject Buffalo (BUF; RT-1b) heart allograft with a mean survival time (MST) of 6.5 +/- 0.5 days. A 14-day i.v.infusion of 0.8 mg/kg RAPA begun on the day of transplantation prolonged the survival to 74.1 +/- 20.2 days (P < 0.001), 0.2 mg/kg to 32.2 +/- 10.0 days (P < 0.001), and 0.08 mg/kg to 36.4 +/- 11.8 days (P < 0.001). When RAPA therapy (0.8 mg/kg) was begun 3 or 4 days after transplantation, the grafts survived 85.2 +/- 31.1 (P < 0.001), and 70.2 +/- 43.3 (P < 0.005) days, respectively. Therapy initiated on day 5 was much less effective; most transplants were rejected within 10 days; one graft survived 32 and two grafts 60 days (MST = 17.6 +/- 20.0, NS). A 0.2 mg/kg RAPA dose prolonged graft survival with initial use on days 3 (31.6 +/- 12.2 days; P < 0.001) or 4 (31.4 +/- 8.1 days; P < 0.001) but not on day 5. The 0.08 mg/kg RAPA prolonged hearts only when started on day 3 (47.2 +/- 2.7 days; P < 0.001) but not on days 4 or 5. WFu recipients treated with a subtherapeutic dose of cyclosporine (1 mg/kg; 9.1 +/- 1.5 days) displayed prolonged heart allograft function when treated subsequently with RAPA (0.8 or 0.08) beginning from days 4, 5, or 6 postgrafting. These in vivo results are supported by in vitro experiments. The frequency of BUF alloreactive elements among normal WFu LN cells (fTc) was 337 +/- 139/10(6) T cells in limiting dilution assay. Addition of RAPA (1 muMol) at the beginning of culture significantly reduced (P < 0.025) the fTc to 17 +/- 6.6/10(6), or alternatively on days 4 or 6 to 37.3 +/- 20.0/10(6) and 58.6 +/- 21.8/10(6), respectively. Thus, both in vivo and in vitro data demonstrate that delayed RAPA therapy may interrupt alloimmune reactions.

Animals↗