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J L Urban

Publications and source records attributed to J L Urban.

At least 19 recordsLinked to original sources
PubMed1996

Immunodominance deters the response to other tumor antigens thereby favoring escape: prevention by vaccination with tumor variants selected with cloned cytolytic T cells in vitro.

Variant cancer cells which arise from the parent tumor during tumor progression can escape immunity but retain antigens. We have mixed highly immunogenic (A+B+) murine parental cancer cells with less immunogenic (A-B+) variant cancer cells to construct a model of a cancer containing escape variants. When such mixtures of cancer cells were injected into normal mice, the variant cells grew out because immune responsiveness to the B antigen on the variant was hindered by dominance of the A antigen on the surrounding parental tumor cells. However, A-B+ variant cells inoculated alone at a separate site induced B specific cytolytic T cells and were rejected. Moreover, mice immunized with A-B+ cells rejected a challenge which contained a mixture of variant and parental cancer cells, while immunization with A+B+ cells was ineffective. Thus, variant tumor cells selected from parental tumor cells by cytolytic T cells in vitro can be used to induce protective immunity against variants expected to escape tumor immunity in vivo. The immunodominance of the A antigen may be related to its ability to induce a much more rapid CTL response than the B antigen, since we show in another model that the pre-existence of a CTL response to one antigen prevented the subsequent induction of CTL to another antigen injected at the same site, even if both antigens were equally efficient at inducing CTL. These results indicate that immunodominance can affect strong as well as weak antigens. Vaccination with individual antigens at separate sites rather than with multiple antigens at one site may, therefore, be needed to prevent tumor escape and tumor recurrence or to counteract infectious diseases.

Animals↗
PubMed1993

A tumor escape variant that has lost one major histocompatibility complex class I restriction element induces specific CD8+ T cells to an antigen that no longer serves as a target.

After loss of expression of a major histocompatibility complex class I Kk allele, the escape variant of an immunogenic tumor grows progressively in normal mice. This progressor variant is resistant to killing by cytotoxic T lymphocytes (CTLs) directed against the A and B antigens presented by Kk. Although the variant retains the expression of the Dk allele and is sensitive to CTLs directed against the C antigen presented by Dk, the variant failed to induce CTLs to this antigen in vivo. Instead, the variant induced CD8+ T cells directed to the A antigen. This was shown at the molecular level by T cell receptor beta chain sequence analysis of the responding cells. Further evidence for the presence of A antigen in the variant came from the finding that spleen cells of mice injected intraperitoneally with the variant tumor cells were primed for an anti-A CD8+ CTL response in vivo. Thus, in contrast to other variants that lost a target antigen and induced a CTL response to remaining target antigens, the Kk loss variant continued to induce an immune response to a tumor antigen that is no longer presented on the tumor cell surface. Even though the variant escapes in a single step because an effective CTL response to secondary antigens is prevented, these secondary antigens remain as potential targets of immunotherapy on the variant's cell surface.

Animals↗
PubMed1993

DNA sequence analysis of T-cell receptor genes reveals an oligoclonal T-cell response to a tumor with multiple target antigens.

Human and murine cancers can express multiple independent antigens as targets for cytolytic T-cells (CTLs). The immune response against one such tumor was studied at the cellular and molecular level by analyzing the T-cell receptor beta chains of CTLs responding in vivo to a murine UV light-induced cancer. A 5-13-fold enhancement of V beta 13+ CTLs above background (naive spleen, 4-5% V beta 13+ among CD8+ T-cells) was demonstrated in the responses of ten individual animals to this tumor. The dominance of V beta 13 usage was exclusively limited to the CD8+ compartment and correlated with recognition of the A but not the B and C antigens on the tumor. In addition, the amino acid sequences of the putative third complementarity determining regions of the T-cell receptor beta chains of CTLs isolated in vivo were remarkably similar to each other suggesting restriction also at the clonal level. Cells responding to four other syngeneic UV-induced tumors, each expressing different unique antigens, or to a variant of the same tumor that had selectively lost the A but retained the independent B and C antigens, induced a 2-fold or less enhancement of V beta 13+ CD8+ cells above background. Thus, the host responds to only one of the several possible target antigens and with relatively few CTL clonotypes.

Amino Acid Sequence↗
PubMed1992

Tumor antigens.

This review solidifies a new concept that common and rare types of human cancers harbor a variety of tumor-specific mutant proteins that may be recognized as tumor-specific antigens. These mutant proteins are encoded by oncogenes or suppressor genes that have undergone structural mutations resulting from point mutations, chromosomal translocations, internal deletions and viral insertional mutagenesis; several of these changes result in fusion proteins. While there is no evidence that immunosurveillance against these mutant proteins can prevent the development of primary cancers without prior immunization of the host, such tumor-specific molecules might be important for diagnosis and as targets for specific immunotherapy once the cancer has developed or even as targets for preventive cancer vaccines. Evidence further supports the notion that cytolytic or helper T cells are exquisitely selective in recognizing intracellular mutant proteins, and tumor-specific T cell clones presently available may become useful for identifying previously unrecognized tumor-specific mutations. Many tumor-specific mutant proteins clearly play a causative role in the establishment of malignant behavior, whereas other carcinogen-induced changes have at least immunological relevance. In any case strong evidence in mouse and man indicates that a single malignant cell can express multiple independent antigenic target sites. Such multiplicity may allow a multi-pronged immune attack that substantially decreases the chance of tumor escape. Future work must explore whether immune responses to tumor-specific mutant proteins can lead to immunological tumor rejection and explore the possibility of chemically engineering tumor mutant peptides to be highly immunogenic, even in hosts that have previously failed to respond to the tumor.

Antigens, Neoplasm↗
PubMed1990

Amino acid variations at a single residue in an autoimmune peptide profoundly affect its properties: T-cell activation, major histocompatibility complex binding, and ability to block experimental allergic encephalomyelitis.

Myelin basic protein (MBP) or helper T cells reactive against MBP induce an autoimmune disease, experimental allergic encephalomyelitis, in B10.PL and PL/J inbred mice. In both strains, virtually the entire repertoire of MBP-specific T cells recognize an N-terminal peptide fragment in the context of the I-Au molecule encoded by the major histocompatibility complex (MHC) and utilize a very limited set of T-cell receptor genes. To delineate the nature of the trimolecular complex, consisting of the T-cell receptor, MBP-peptide fragment, and MHC molecule (I-Au), we have synthesized 13 variants of the 9-mer N-terminal immunodominant peptide differing at residue 4 and studied their immune recognition in vitro and in vivo. These substitutions have a striking range of effects on T-cell activation, ability to bind to the MHC molecule, and initiation of immune responses in vivo. An understanding of the autoimmune peptide/MHC/T-cell receptor interactions allowed us to design variant 9-mer peptides that have high affinity for an MHC molecule and are effective in blocking experimental allergic encephalomyelitis, possibly through two distinct mechanisms, peripheral T-cell tolerance and the inhibition of binding of the encephalitogenic peptide to the MHC molecules.

Amino Acid Sequence↗
PubMed1989

In individual T cells one productive alpha rearrangement does not appear to block rearrangement at the second allele.

The T cell lymphoma line BW5147 has rearranged TCR alpha chain genes segments on both the homologous chromosomes: one is functional (V alpha 1) and the second (V alpha 16.1) is a pseudogene. The extreme 3' position of the V alpha 16.1 gene segment in the V alpha locus allows us to recognize rearrangements of most V alpha gene segments using the V alpha 16 probe as a marker. The absence of the genomic V alpha 16.1 gene fragment in mature thymocytes, antigen-specific T cells, and in more than two-thirds of the peripheral T cells suggests that most T lymphocytes rearrange both alpha loci. It appears that productive alpha chain rearrangement on one allele probably does not block a subsequent rearrangement on the other alpha locus.

Alleles↗
PubMed1989

Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy.

Experimental autoimmune encephalomyelitis (EAE) results from T helper (TH) cell recognition of myelin basic protein (MBP). We have characterized TH cell reactivity in B10.PL and PL/J (H-2u) mice to 39 N-terminal MBP peptide derivatives of different lengths and with individual amino acid substitutions. The peptide determinant of murine MBP can be divided into a minimal stimulatory core region (residues 1-6) and a tail region (residues 7-20) that alters the structure of the core region to affect both T cell recognition and MHC binding. Core recognition by B10.PL and PL/J mice is highly similar but in one case strain dependent. Peptide analogs that do not stimulate MBP-specific TH cells but bind to the I-Au molecule competitively inhibit T cell reactivity to MBP in vitro and prevent the induction of EAE in vivo.

Amino Acid Sequence↗
PubMed1989

Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype.

T helper cells reactive to myelin basic protein are clearly implicated in the pathogenesis of murine EAE. We have developed a T cell line, BML-1 that (1) is reactive to the encephalitogenic amino terminal nonapeptide (1-9NAC) of MBP, (2) is I-Au restricted, and (3) induces relapsing EAE in B10.PL (H-2u) mice. Measurement of the lymphokine profile of BML-1 revealed secretion of IL-2, interferon-gamma and lymphotoxin but not IL-4. This profile is consistent with the Th1/DTH subtype. Coculture of BML-1 with MBP-primed B cells shows that BML-1 does not provide significant helper function in vitro. In addition, BML-1 secretion of interferon-gamma was found to inhibit LPS-induced anti-MBP antibody responses. This suggested that anti-MBP antibodies may not be necessary for induction of EAE. Sera from mice, in which severe disease was induced with the 1-9NAC peptide and Bordetella pertussis, showed no development of serum antibodies to MBP. These data show that MBP-reactive Th cells of the Th-1/DTH subtype can induce EAE and do not provide Th function for anti-MBP responses and that serum anti-MBP antibodies are not found in peptide 1-9NAC-induced disease. T cell lines specific for encephalitogenic epitopes and characterized for lymphokine secretion will provide a useful tool for understanding the role of T cells in the induction of EAE.

Animals↗
PubMed1988

Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy.

Experimental allergic encephalomyelitis (EAE) is a paralytic autoimmune disease induced in susceptible animals by active immunization with myelin basic protein (MBP) or by passive transfer of MBP-specific T helper (TH) lymphocytes. We have analyzed the T cell receptor genes of 33 clonally distinct TH cells specific for a nonapeptide of MBP inducing EAE in B10.PL (H-2u) mice. All 33 TH cells used two alpha variable gene segments (V alpha 2.3, 61%; V alpha 4.2, 39%), the same alpha joining gene segment (J alpha 39), and two V beta and J beta gene segments (V beta 8.2-J beta 2.6, 79%; V beta 13-J beta 2.2, 21%). The anti-V beta 8 monoclonal antibody F23.1 was found to block completely recognition of the nonapeptide by V beta 8 TH cells in vitro and to reduce significantly the susceptibility of B10.PL mice to peptide-induced EAE.

Animals↗
PubMed1988

Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice.

Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS) that occurs after immunization of animals with myelin basic protein (MBP). The disease is a prototype model for the study of antigen-specific T helper cell-mediated autoimmune disease. In SJL/J mice, EAE is mediated by T helper cells directed against a 40-amino acid COOH-terminal peptic fragment of mouse small MBP. To identify the minimal T cell epitopes of MBP responsible for EAE, overlapping peptides completely encompassing the epitopes within this region were synthesized. A 28-residue peptide of mouse MBP spanning residues 87-114 (pM87-114) was able to elicit both a strong T cell response and chronic relapsing disease. To better localize the T cell epitopes, shorter peptides within this region were synthesized and two overlapping peptides, pM87-98 and pM91-104, were able to induce EAE. T cell clones and bulk lymph node cell populations reactive with pM87-98 did not respond to pM91-104. However, lymph node cells reactive with pM91-104 also reacted with pM87-98, thus showing that these two peptides represent contiguous, but distinct encephalitogenic epitopes and that both these epitopes may be contained within pM87-98. In addition, pM87-114 and pM87-98 were found to be minor determinants of the total T cell response to rat and rabbit MBP. The restricted response to MBP in SJL/J mice is similar to that of the PL/J mice in that each appears to have only a single peptide region in MBP that elicits encephalitogenic T cells. However, within the region studied, there were two if not more T cell epitopes. This differs from the single encephalitogenic PL/J epitope. These findings of a single encephalitogenic peptide region with multiple T cell epitopes and the fact that encephalitogenic T cell epitopes may be subdominant have implications for the design of treatments directed at the T cell receptor-MHC-peptide epitope complex in autoimmune disease.

Animals↗