Paul von Hoegen - Academia.edu (original) (raw)

Papers by Paul von Hoegen

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1998

From a cross between a tumor-susceptible mouse strain (DBA/2; D) and a tumor-resistant MHC-identi... more From a cross between a tumor-susceptible mouse strain (DBA/2; D) and a tumor-resistant MHC-identical strain (B10.D2; D2) new recombinant inbred mouse strains were established over many generations of inbreeding and tumor resistance selection. Since resistance to the highly metastatic DBA/2 lymphoma variant ESb had an immunologic basis, and the two parental strains differed in endogenous viral superantigens (vSAGs), DNA of three D2 x D recombinant inbred mouse lines was typed for endogenous mouse mammary tumor viruses using mouse mammary tumor virus long terminal repeat- and env gene-specific probes. The resistant D2 x D mice were very similar to the susceptible parental strain D in their Mtv Southern blots, except for the lack of a single band corresponding to Mtv-7, the provirus coding for the strong DBA/2 superantigen Mls-1a. A backcross analysis revealed that Mtv-7-negative F2 mice were significantly more resistant than Mtv-7-positive F2 mice. When Mtv-7 was reintroduced into the...

Nature, 1992

Immunology Letters, 1995

Differentiation of cytolytic T cells can be supported by type I and type II interferons (IFN). To... more Differentiation of cytolytic T cells can be supported by type I and type II interferons (IFN). To characterize the role of type I interferons further we tested the role of recombinant IFN-alpha and IFN-beta on the induction of a weak immune response, against a low immunogenic tumor, which has been shown to be increased by IFN. Both type I interferons IFN-alpha and IFN-beta were able to support the differentiation of cytolytic T lymphocytes (CTL). In case of IFN-alpha no correlation with the antiviral activity could be seen by comparison of IFN-alpha1 and IFN-alpha4. The maximal in vitro effects were achieved with very low concentrations in the range of 1-100 IU/ml. IFN-alpha showed the strongest effects, if added in the early phase of the mixed leukocyte culture, whereas IFN-beta was most effective when given at the last day the culture. In combination, both IFNs gave additional/synergistic effects, whereby addition of IFN-alpha at day 0 and IFN-beta at day 4 led to maximal specific CTL responses. In vivo augmentation of the anti-tumor immune response by both types of IFNs supported the in vitro findings and also the synergistic effect of both types of IFNs could be demonstrated. Therefore we propose that IFN-alpha is relevant in the induction of CTL responses, i.e., the conversion of precursor T cell into mature cells and growth promotion whereby IFN-beta might trigger the lytic machinery of the cells and promote differentiation. This synergistic efficacy is also operative in tumor rejection.

European Journal of Immunology, 1989

Previously we described a monoclonal antibody (mAb 12-15) that reacted with murine Fc receptor pr... more Previously we described a monoclonal antibody (mAb 12-15) that reacted with murine Fc receptor proteins (betal, beta2 and alpha) and an undefined molecule of 37 kDa (beta3) on certain types of cells. Here we present serological and biochemical evidence that the beta3 chain is expressed on mouse thymocytes and that it is identical to the CD2 antigen. By immunofluorescence staining and cytofluorographic analysis > 95% of thymocytes were positive. Brightly staining cells coincided with cortisonresistant thymocytes suggesting that mature thymocytes ex ressed higher levels of the antigen. Biosynthetic labeling of DBN2 thymocytes with ['Slmethionine showed that the size of the CD2 precursor molecule was 43 kDa which was processed to approximately 55-65 kDa in the mature molecule. mAb12-15 was also reactive with the tunicamycin-treated form of the CD2 antigen suggesting that the cross-reactive epitope was of protein nature. Comparison of different mouse strains indicated that two molecular forms of CD2 exist. On BALB/c thymocytes, the relative mass of the native molecule was approximately 60-70 kDa (CD2.1) and slightly larger than in DBN2 (CD2.2). Following endoglycosidase F treatment both proteins still showed a slight difference in electrophoretic mobility. Several inbred mouse strains were analyzed for expression of CD2 forms. When mAb 12-15 was used in cyotoxic T lymphocyte inhibition experiments using specific CTL and tumor target cells it was found that the antibody could specifically inhibit CTL-mediated lysis presumably by interfering with CD2 function.

European Journal of Immunology, 1988

Viral modification increases the frequency of tumor-specific CTL * This work was supported by a g... more Viral modification increases the frequency of tumor-specific CTL * This work was supported by a grant from the DFG (Schi 4614-2) and by the Wilhelm Sander Stiftung. Correspondence: Volker Schirrmacher, Deutsches Krebsforschungszentrum, Institut f i r Immunologie und Genetik, Im Neuenheimer Feld 280, D-6900 Heidelberg, FRG Abbreviations: CTL: Cytotoxic T lymphocytes pCTL: Precursor CTL HU. Hemagglutination units IL 2: Interleukin 2 LDA: Limiting dilution analysis LU: Lytic units MLC: Mixed leukocyte culture MLTC: Mixed leukocyte tumor cell culture NDV: Newcastle Disease Virus TATA: Tumor-associated transplantation antigen IL2 Interleukin 2 lo, 2": Primary and secondary immunization 0 VCH Verlagsgesellschaft mbH, D-6940 W&nheim, 1988

Cellular Immunology, 1987

The specific immune response against syngeneic tumors by T cells is dependent on the existence of... more The specific immune response against syngeneic tumors by T cells is dependent on the existence of tumor-associated transplantation antigens (TATA). In the case of the chemically induced DBA/2-derived lymphoma Eb and its highly metastatic variant ESb the immunogenicity of these antigens is not sufficient to prevent tumor growth. Therefore we tested in two systems the influence of additional antigens as possible helper determinants for the generation of tumor-specific immune responses. In the Eb tumor system additional antigens were induced by mutagenization. The frequency of cytotoxic T lymphocytes (CTL) in response to mutagenized Eb cells was higher than that in response to untreated Eb cells. Fine specificity analysis revealed there there was no increase in the CTL response against the original TATA, but an activation of additional CTL clones responding to mutagen-induced antigens. In the ESb tumor system we tested the effect of additional recognition of minor histocompatibility antigens on the frequency of TATA-specific CTL. Transplantation of ESb tumor cells into B10.D2 mice, which are H-2-identical but differ in minor antigens, results in strong tumor rejection responses. In a limiting dilution mixed-leukocyte-tumor microculture system it was found that the minor antigens are recognized at the clonal level as independent antigens. The overall frequency of anti-tumor CTL in ESb-immunized B10.D2 mice was about 1/3000. Among these, the frequency of TATA-specific CTL was 1/16,709 and thus not significantly different from that of syngeneic DBA/2 mice. Thus neither minor antigens nor mutagen-induced antigens acted in the Eb/ESb tumor system as helper determinants and did not increase the frequency of tumor-specific CTLs.

Advanced Drug Delivery Reviews, 2001

For the optimal delivery of antigens to mucosal tissues, especially as nasal sprays, protein anti... more For the optimal delivery of antigens to mucosal tissues, especially as nasal sprays, protein antigen alone is often not sufficient. A clear need for nasal delivery systems has therefore evolved, especially for Influenza A vaccines. Such technologies will be even more essential for new modern vaccines based on recombinant antigens. Here we describe synthetic biomimetic supra molecular Biovector (SMBV) which have proven in preclinical and clinical evaluation to be suitable candidates for the delivery of nasal vaccines. They also demonstrate the potential to work with multiple antigens and furthermore allow combination with adjuvants. These Biovectors can associate with internal or lipid layer membrane proteins and peptides due to their charged polysaccharide core. The mimicry with viruses is also provided through their size of 60-80 nm, which allows sterilization by filtration. This makes them an ideal tool for the development of modern nasal vaccines, as they have shown to be able to induce the desired types of humoral immunity (serosal and mucosal immunity, IgA and IgG antibodies) as well as cellular immunity (CD4 and CD8 responses).

Journal of Experimental Medicine, 1989

We have examined the ability of hCD4 to interact functionally with mouse class II MHC molecules u... more We have examined the ability of hCD4 to interact functionally with mouse class II MHC molecules using the mouse T cell hybridoma BI-141, specific for beef insulin. We have previously shown that expression of mouse CD4 results in a marked enhancement of IL-2 release by BI-141 cells in response to beef insulin or, in a cross-reactive response, to pork insulin, on the appropriate mouse APCs. We now demonstrate that expression of hCD4 results in an equivalent stimulation of antigen responses by this mouse T cell hybridoma. The specificity of this effect was demonstrated by mAb and gp120 blocking studies. These data provide the first direct evidence for function of hCD4 and in an exclusively mouse system.

Journal of Cancer Research and Clinical Oncology, 1995

Without Abstract

Journal of Cancer Research and Clinical Oncology, 1995

International Journal of Cancer, 1986

Effective anti-metastatic therapy was achieved in a mouse tumor model by combining surgery with p... more Effective anti-metastatic therapy was achieved in a mouse tumor model by combining surgery with postoperative immunotherapy using virus-modified autologous tumor cells. No therapeutic effect was observed when using for immunotherapy the nonmodified autologous tumor ESb, which is only weakly immunogenic and highly metastatic. The viral modification was achieved by infecting the tumor with an avirulent strain of Newcastle disease virus (NDV), which led to expression of viral antigens and to an increase in the tumor cells' immunogenicity. Parameters which were of decisive influence for success or failure of therapy were the time of operation of the primary tumor and the dose of virus which was admixed t o a standard dose of irradiated tumor cells. There was a low dose optimum of NDV at about 100 hemagglutinating units per 25 x lo6 tumor cells. The therapeutic effect observed was less pronounced if the virus was given separately from the tumor cells. Postoperative immunotherapy with NDV-modified tumor cells had the following therapeutic effects: (I) disappearance of micrometastases from visceral organs as ascertained by a sensitive bioassay; (2) life prolongation in virtually all animals when compared t o controls (operated only); (3) cures in about 50% of the treated animals. The possible mechanism of this therapeutic effect and its potential for clinical application are discussed.

International Journal of Cancer, 1994

To study metastasis at the single-cell level we transduced highly metastatic ESb lymphoma cells w... more To study metastasis at the single-cell level we transduced highly metastatic ESb lymphoma cells with a retroviral expression vector containing the lacZ (bacterial fi-galactosidase) gene. This allowed single ESb-lacZ tumor cells to be detected in infiltrated target organs by means of X-Gal staining. Despite expression of the lacZ gene, the tumor cells were still tumorigenic, highly metastatic, unchanged in phenotype and therefore comparable to parental ESb cells. After spontaneous metastasis, whole-organ staining revealed metastatic foci at the surface of the liver. In histological liver sections, metastatic clusters and single dispersed tumor cells could be detected. In contrast to whole-organ staining, histological examination revealed scattered distribution of tumor cells throughout the organ, which was not evident with parental ESb cells. In addition, clusters with diffuse or dense (focal) appearance were found, in correlation with the whole-organ staining. Expression of the foreign lacZ gene allowed the metastatic spread of tumor cells to liver and spleen to be quantified approximately by FACS analysis. Furthermore, it was shown that the newly expressed P-gal was expressed not only intercellularly but also at the cell surface. There it could be recognized by MAbs and cytotoxic T-cells (CTL). @-gal did not affect CTL recognition of the ESb tumorassociated antigen. In conclusion, lacZ could be used as a genetic marker for a highly metastatic lymphoma, to define scattered metastatic spread in the liver at the single-cell level and to quantify the tumor load by FACS analysis.

Gene Therapy, 1998

Three different vaccination sites were compared for efficiency of immunization with naked DNA. Us... more Three different vaccination sites were compared for efficiency of immunization with naked DNA. Using the bacterial lacZ gene as a model, all three sites of the mouse (skeletal muscle, dermis of abdominal skin or of the ear pinna) could express the gene product beta-gal but varied in expression time with muscle tissue showing the longest expression. Expression time, however, did not correlate with immune response intensity. The ear pinna was by far the most effective and muscle the least effective priming site for specific humoral and cytotoxic T cell-mediated immune responses. Following intra-pinna DNA inoculation, beta-gal expressing cells were detectable around the injection site and in the major draining lymph node. Efficiency of immunization was also dependent on the promoter and expression vector used. The cytomegalus virus promoter driven pCMV beta vector was superior to the Moloney murine leukemia virus LTR driven BAG vector. LacZ DNA immunization was also compared with cell-based vaccination with lacZ-transfected tumor cells, in which case again the pinna was the best site for inducing strong immune responses. Tumor-specific T cell responses could also be well induced in the pinna, leading to cytotoxic T lymphocyte induction and protective antitumor immunity. Thus, the pinna was found to be a privileged site for induction of antitumor responses and for genetic immunization, an important finding of immediate practical and potential future clinical implications.

European Journal of Immunology, 1993

In attempt to increase the induction of peptide-specific cytolyticT cells (CTL) we investigated t... more In attempt to increase the induction of peptide-specific cytolyticT cells (CTL) we investigated the effect of the Newcastle disease virus (NDV) hemagglutininneuraminidase (HN) gene product on the activation of peptide-specific CTL. Spleen cells of CH3 mice immunized against the influenza nucleoprotein peptide 50-63 (NP 50-63) were restimulated in vitro (i) with peptide-pulsed syngeneic fibroblast cells (Ltk-) as antigen-presenting cells, which were in addition (ii) infected with NDVor (iii) stably transfected with the HN cDNA of NDV. A greater than sixfold increase in peptide-specific CTL responses was observed in cultures restimulated with peptide-pulsed Ltk-cells which coexpressed viral hemagglutinin due to either infection or transfection. A similar augmentation was seen in CTL responses against other types of antigen (major histocompatibility complex alloantigens, minor histocompatibility antigens or tumor antigens) when suboptimal cultures were stimulated with the respective antigen-presenting cells modified by NDV infection. These findings suggest that NDVor viral HN expressed on antigen-presenting cells or tumor cells can exert a T cell co-stimulatory function.

Gene Therapy, 2000

To optimize polynucleotide vaccinations for protective antitumor immunity we used a self-replicat... more To optimize polynucleotide vaccinations for protective antitumor immunity we used a self-replicating RNA vaccine in which Semliki Forest virus replicase drives RNA expression of the lacZ gene coding for ␤-galactosidase as model tumorassociated antigen (TAA). This was compared with replicase-deficient control RNA and with lacZ DNA plasmids with respect to gene expression in vitro and in vivo and for vaccination using the mouse ear pinna as an optimal immunization site. In vitro, the highest expression was observed with self-replicating RNA. Gene expression following pinna inoculation of either non-replicating DNA plasmids or self-replicating RNA was similar, lasting for 2-3 weeks. Higher antibody responses were obtained with RNA than with DNA. ␤-Gal peptide specific CTL memory responses to lacZ DNA or RNA lasted for more than 6 weeks while respective responses induced by lacZ-transfected tumor cells lasted for only 2 weeks. To achieve a protective response against lacZ tumor cells with self-replicating RNA

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1998

Nature, 1992

Immunology Letters, 1995

European Journal of Immunology, 1989

European Journal of Immunology, 1988

Cellular Immunology, 1987

Advanced Drug Delivery Reviews, 2001

Journal of Experimental Medicine, 1989

Journal of Cancer Research and Clinical Oncology, 1995

Without Abstract

Journal of Cancer Research and Clinical Oncology, 1995

International Journal of Cancer, 1986

International Journal of Cancer, 1994

Gene Therapy, 1998

European Journal of Immunology, 1993

Gene Therapy, 2000