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Biomedical subjects

D A Carlow

Publications and source records attributed to D A Carlow.

22 records · Page 2Linked to original sources
PubMed1985

Enhanced expression of class I major histocompatibility complex gene (Dk) products on immunogenic variants of a spontaneous murine carcinoma.

Both immunogenic and nonimmunogenic variant clones were isolated from a recently obtained spontaneous murine adenocarcinoma after treatment (xenogenization) with either the mutagen ethyl methanesulfonate or the DNA hypomethylating agent, and "gene activator," 5-azacytidine. Clonal analysis of the untreated tumor population confirmed that immunogenic variants arose as a consequence of the xenogenization protocol. At a dose of 10(6) cells per mouse, nonimmunogenic variants, like the parental tumor line, grew progressively in normal syngeneic recipients. In contrast, immunogenic variants were rejected in normal syngeneic mice and grew progressively only in T-cell-deficient nude mice. Serologic analysis of the respective clonal variants revealed that immunogenic variants expressed substantially elevated (fourfold to tenfold) levels of class I H-2Dk antigen relative to parental or nonimmunogenic cell lines. Two variants exhibiting marginal immunogenicity expressed high and low levels of major histocompatibility complex (MHC) antigen, respectively suggesting that elevated MHC expression, although possibly a contributing factor, did not account for the immunogenic phenotype in all cases. Finally, the immunogenic phenotype of two variants decayed with time in culture. Clones in the process of reversion lost their elevated Dk gene expression and became progressively more tumorigenic in normal syngeneic mice. Together, these data are consistent with a hypothesis that elevated MHC expression can contribute to the immunogenic phenotype of originally low MHC-expressing tumors and that the reduced level of MHC observed in certain clinical cancers may have significant implications with regard to immunologic aspects of the tumor-host relationship.

Animals↗
PubMed1984

Possible epigenetic mechanisms of tumor progression: induction of high-frequency heritable but phenotypically unstable changes in the tumorigenic and metastatic properties of tumor cell populations by 5-azacytidine treatment.

Treatment of a variety of highly tumorigenic mouse lines in vitro with chemical mutagens, such as ethyl methane sulfonate (EMS) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), can result in extraordinarily high frequencies (sometimes in excess of 90%) of strongly immunogenic clones unable to grow progressively in normal syngeneic hosts. These clones will, however, grow in immunosuppressed hosts and gradually regain tumorigenic ability in normal mice if maintained in long-term (several months-1 year) culture, i.e., they are often phenotypically unstable. These features--phenotypic drift and high frequency--make it unlikely that point mutations are the underlying mechanism involved in the generation of the variants. Results presented here demonstrate that these observations can be reproduced on the same tumor lines using 5-azacytidine--an analogue of cytidine which can be incorporated into DNA causing subsequent extensive hypomethylation of cytosine residues in the absence of any significant mutagenic effects. Furthermore, 5-azacytidine treatment of a nonmetastatic mouse mammary tumor led to the emergence of a small number of heritable but unstable tumor clones capable of spontaneous metastatic spread. Because it is known that DNA hypomethylation can lead to transcriptional activation of normally silent genes, that altered methylation patterns can be somatically replicated with a high but not perfect fidelity, and that mutagens can cause DNA hypomethylation, we propose that DNA hypomethylation followed by de novo methylation represents a plausible mechanism to account not only for the induction of the nontumorigenic variants but for a number of aspects of tumor progression and tumor heterogeneity, as well. In particular, we refer to heritable phenotypic alterations in tumor cell populations which occur at very high frequency but which are not necessarily stable over very long periods of time.

Animals↗
PubMed1982

T cell idiotypes recognizing self-major histocompatibility complex molecules: H-2 specificity, allotype linkage, and expression on functional T cell populations.

An anti-idiotypic serum (antiserum 5936, B. Rubin et al., J. Exp. Med. 1979. 150: 307) was used to demonstrate receptor sites for self-major histocompatibility complex (MHC) antigens on T lymphocytes. The antiserum was raised by injecting rabbits tolerant to mouse Ig with a B6 anti-CBA (anti-H2k) alloantibody. It recognized a large proportion of T cells from H-2k strains carrying the b, c, d or e allele at the Igh-1 locus, but only a few T cells from H-2k strains with Igh-1 alleles a, f and j. Allotype linkage of the 5936 idiotype was also demonstrated by segregation analysis. The antiserum did not recognize either H-2k B cells or T cells from other H-2 haplotypes despite the presence of a permissive Igh-1 allele. The 5936 idiotype was found to be associated with several different antigen specificities, indicating that it is not located on the binding site for foreign antigen. Furthermore, the 5936 antiserum inhibited the binding of soluble Ik antigens by H-2k, Igh-1b, T cells, and, in the presence of complement, eliminated T cells responding to different antigens in an I-Ak-restricted fashion. Collectively, the data indicate that the structure bearing the 5936 idiotype is a receptor for I-Ak antigens, expressed by strains carrying the I-Ak allele and a permissive allele at the Igh-1 locus. The relevance of this finding to the MHC-restricted recognition of antigens by T cells is discussed.

Animals↗