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H J Stauss

Publications and source records attributed to H J Stauss.

48 records · Page 3Linked to original sources
PubMed1990

Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen.

Breaking the state of immunological unresponsiveness of tumor-bearing individuals to cancer is a prerequisite for active or passive tumor-specific immunotherapy. To study this problem the immunogenic MHC class I antigen, K216 was transfected into a progressor tumor. The transfected tumors were regularly rejected by normal mice but grew progressively in mice bearing nontransfected tumors. In addition, transgenic mice were derived to obtain normal cells and tissues expressing the same K216 gene product. Normal mice rejected K216-positive normal or malignant tissue grafts and generated K216-specific CTL in vitro and in vivo in response to these challenges. In contrast, mice bearing nontransfected tumors, though rejecting K216-positive nonmalignant tissue grafts, did not reject K216-positive tumors nor generate K216-specific CTL in response to K216-positive tumor cells. Mice bearing K216-positive tumors also rejected the nonmalignant K216-positive tissue grafts, but this in vivo response failed to lead to rejection of the simultaneously present tumor graft expressing the same antigen; in fact, immunity had no measurable effect whatsoever on tumor size or incidence and caused no selection for antigen loss variants. Taken together, the present findings suggest that transfer of expression of a target antigen into nonmalignant cells provides a way for obtaining effective stimulation of antigen-specific CTL in tumor-bearing mice, but that additional manipulations will be required to cause immunological rejection of established tumors.

Animals↗
PubMed1989

The alpha 3 domain of major histocompatibility complex class I molecules plays a critical role in cytotoxic T lymphocyte stimulation.

Allogeneic major histocompatibility complex class I molecules induce strong cytotoxic T lymphocyte (CTL) responses whereas xenogeneic molecules do not. We have tested a series of mouse/human hybrid molecules for their ability to stimulate mouse CTL. The molecules with murine alpha 3 domains consistently stimulated stronger CTL responses than those with human alpha 3 domains, independent of the species origin of the N-terminal alpha 1 or alpha 2 domains. We have found that the ability of class I molecules to induce strong cytotoxic responses correlates positively with their ability to stimulate expansion of the CD8+CD4-T cell subset. The results indicate that mouse T cells can recognize class I molecules with human alpha 1 and/or alpha 2 domains, but for efficient stimulation of these T cells it is important that the immunizing molecule contains a murine alpha 3 domain. We suggest that T cell priming requires an efficient interaction of CD8 with the class I alpha 3 domain, and this shows some species restriction.

Animals↗
PubMed1987

DNA sequence analysis of the C3H H-2Kk and H-2Dk loci. Evolutionary relationships to H-2 genes from four other mouse strains.

We generated nucleotide sequences for H-2Kk and H-2Dk from the C3H mouse, as well as for a genomic clone of H-2Db, in order to conduct an evolutionary analysis of the H-2 genes from three haplotypes, k, d, and b. H-2Kk from both the C3H and AKR strains, H-2Kd, H-2Kb, H-2Dk, H-2Ld, H-2Dd, H-2Db, and H-2Dp DNA sequences were aligned, and the alignments used to construct phylogenetic trees inferring the evolutionary relationships among the nine genes by two independent methods. Both approaches yielded trees with similar topologies. In addition, the sequence alignments revealed patterns of nucleotide substitutions which implicate both point mutation and recombination in the divergence of the H-2 genes. Future considerations for evolutionary analysis of class I genes are discussed.

Amino Acid Sequence↗
PubMed1986

Identification of a unique tumor antigen as rejection antigen by molecular cloning and gene transfer.

Tumor-specific transplantation antigens are antigens that can lead to complete immunological destruction of a transplanted cancer by the syngeneic host. When such antigens are expressed on cancers induced by chemical or physical carcinogens, then they are usually unique, i.e., antigenically different for each independently induced tumor. In this study, we show that the product of a gene encoding a novel MHC class I molecule and isolated from the murine UV light-induced regressor tumor 1591 represents one such unique tumor-specific transplantation antigen that causes tumor rejection. The major evidence comes from our finding that 1591 progressor variants regularly lost the gene encoding this antigen that is expressed in the parental tumor that regresses in normal mice; furthermore, reintroduction of this gene into a 1591 progressor variant by DNA transfection caused the progressor variant to regress in normal immunocompetent mice. Thus, the progressor tumor reverted to the parental regressor phenotype following transfection. Consistent with the conclusion that the expression of the novel MHC class I gene following transfection was responsible for the regressor phenotype is also our finding that a variant of the transfected tumor that had lost expression of the transfected gene resumed its progressive growth behavior. Finally, we show that the molecule encoded by the novel class I gene is specifically recognized by a syngeneic tumor-specific cytolytic T cell clone that we have previously shown to select in vitro for progressor variants from the parental regressor tumor cell line. It remains to be determined to what extent unique tumor-specific rejection antigens of other highly immunogenic regressor tumors are encoded by novel MHC class I genes and whether these genes represent germline mutations or somatic mutations caused by the carcinogen treatment.

Animals↗
PubMed1985

Dissection of tumour-specific antigenicity.

Unique tumour-specific antigens have been detected on many tumours induced by physical or chemical carcinogens. Although a seemingly endless diversity of such antigens has been identified, very little is currently known about the nature and complexity of the antigenicity of any single tumour. We describe the characterization of the complex unique antigenicity expressed on an ultraviolet-light-induced tumour. Such tumours are highly immunogenic and are clearly subject to immunosurveillance in the normal host. The antigenicity of an ultraviolet-light-induced regressor tumour was dissected with the aid of monoclonal T-cell probes and with antigen-loss tumour variants that were selected in vitro or in vivo. It was demonstrated that the total antigenicity of this tumour consisted of multiple antigens, all of which were independent, tumour-specific and expressed simultaneously on the same tumour cell. Additional experiments determined which antigens were critical for tumour rejection by studying the in vivo growth behaviour of antigen-loss variants selected in vitro. Evaluation of the complexity of the host anti-tumour response revealed that a hierarchy existed in the host recognition of these antigens, a finding that should have important implications on the effectiveness of tumour rejection and immune escape. Finally, using tumour-specific monoclonal antibodies against the syngeneic tumour, investigation into the molecular nature of these tumour antigens indicated that some of these antigens represent novel class I major-histocompatibility-complex molecules. Thus we describe the complexity of a unique tumour-specific antigen and discuss the implications of this complexity on tumour immunity and tumour escape.

Animals↗
PubMedDate not supplied

WT1-targeted immunotherapy of leukaemia.

Since malignant cells are derived from normal cells, many tumour-associated antigens are also expressed in normal tissues. For examples, WT1 is expressed at elevated levels in most leukaemias, but it is also expressed at reduced levels in normal CD34+ haematopoietic stem cells and in progenitor cells of other tissues. Antigen expression in normal tissues is likely to trigger immunological tolerance and thus blunt T cell responses. This could explain the observation that WT1 vaccination in mice frequently fails to stimulate high avidity cytotoxic T cell responses. In order to circumvent tolerance, we have isolated from HLA-A2-negative donors high avidity CTL specific for HLA-A2-presented peptide epitopes of WT1. These allorestricted CTL efficiently kill HLA-A2-positive leukaemia cells but not normal CD34+ haematopoietic stem cells. However, adoptive cellular therapy with allorestricted CTL could only be performed in leukaemia patients rendered tolerant to the infused CTL by prior allogeneic stem cell transplantation. In order to circumvent this limitation, we propose to exploit the TCR of allorestricted CTL as therapeutic tool. TCR gene transfer can be used to take advantage of the specificity of allorestricted CTL and transfer it to patient CTL, while avoiding the transfer of immunogenic alloantigens from the donor CTL to the patient.

Animals↗
PubMedDate not supplied

A novel MHC class I molecule as a tumour-specific antigen. Correlation between the antibody-defined and the CTL-defined target structure.

Ultraviolet light (UV)-induced tumours in mice are often highly immunogenic and have unique (individually specific) antigens which cause tumour rejection in normal mice. The molecular nature of these unique 'rejection' or 'transplantation' antigens is not known. We have recently isolated a syngeneic monoclonal antibody (mAb), CP28, that recognizes a unique tumour-specific antigen on the UV-induced regressor tumour 1591-RE. Further analysis revealed that the antibody-recognized antigen represents a novel major histocompatibility complex (MHC) class I molecule. However, the relationship of this molecule to the unique T cell-recognized antigen that causes tumour rejection remained unresolved. In this study we have explored the relationship of the antibody-defined tumour-specific novel class I molecule to the rejection antigen, that we have previously defined with a cytolytic T cell (CTL) clone ('anti-A'). Two different lines of evidence suggested a close relationship. First, it was found that random subclones of the 1591-RE tumour expressed different levels of the CP28-defined antigen which correlated with the level of lysis by the anti-A CTL clone. Second, the selection of antigen-loss variants using either the anti-A CTL clone or the mAb CP28 resulted in the simultaneous loss of both the CP28 as well as the 'A' antigen. This tight correlation strongly suggests a relationship between the antibody-defined and the T cell-defined antigen. However, the role of the antibody-recognized antigen in causing transplantation rejection still needs to be determined.

Animals↗
PubMedDate not supplied

Isolation of the MHC genes encoding the tumour-specific class I antigens expressed on a murine fibrosarcoma.

The C3H UV-induced fibrosarcoma, 1591, is highly immunogenic and, therefore, is readily rejected when transplanted into immunocompetent syngeneic recipients. Previous analysis of 1591 with tumour-specific or H-2-reactive monoclonal antibodies revealed that this antigenicity might be due to the expression of two novel class I major histocompatibility complex (MHC) antigens. In this report we describe the molecular cloning and initial characterization of three genes which account for all of the unique serological class I reactivities observed on this tumour. These include two distinct, but highly conserved, H-2L-like genes, and a third gene the product of which bears determinants which are characteristic of both the tumour and of class I products of the H-2k haplotype. Moreover, each of these genes contains a polymorphic restriction enzyme fragment which is detected in the class I sequences of 1591 relative to normal C3H tissue. Since the expression of these polymorphic class I sequences is relevant to the immunogenicity of 1591, the mutational events by which these genes were generated may be significant to the immunobiology of this tumour.

Animals↗
PubMedDate not supplied

Use of the allogeneic TCR repertoire to enhance anti-tumor immunity.

It is well established that antigen-specific T lymphocytes can inhibit tumor growth in humans and in mice, leading to complete tumor elimination in some cases. However, in many cases T cell immunity is unable to successfully control tumor progression. Since tumors are derived from normal tissues, most antigens are shared with normal tissues, although expression levels are usually elevated in malignant cells. Nevertheless, low-level expression in normal cells can be sufficient to render autologous T cells tolerant and thus unable to mount effective immune responses against tumors. Here, we review how allogeneic T cells can be used to isolate T cells that effectively recognise and kill tumor cells, but not normal cells with low level of antigen expression. The TCR of allogeneic T cells can be introduced into patient T cells to equip them with anti-tumor specificity that may not be present in the autologous T cell repertoire.

Graft vs Host Disease↗