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F Momburg

Publications and source records attributed to F Momburg.

At least 73 records · Page 4Linked to original sources
PubMed1991

Exogenous peptides compete for the presentation of endogenous antigens to major histocompatibility complex class II-restricted T cells.

Antigen-presenting cells (APC) transfected with a construct encoding the hen egg-white lysozyme (HEL) amino acid sequence 1-80 constitutively present HEL peptides complexed to major histocompatibility complex (MHC) class II molecules to specific T cell hybridomas, indicating that endogenous cellular antigens can be efficiently presented to class II-restricted T cells. Here we show that exogenous peptide competitors added to HEL-transfected APC can inhibit the presentation of endogenous HEL peptides to class II-restricted T cells. The inhibition is specific for the class II molecule binding the competitor peptide, and it affects to the same extent presentation of exogenous or endogenous HEL peptides. These results, demonstrating that an exogenous competitor can inhibit class II-restricted T cell activation induced by endogenous as well as exogenous antigen, suggest lack of strict compartmentalization between endogenous and exogenous pathways of antigen presentation. Since autoreactive T cells may recognize endogenous, as well as exogenous antigens, the results have implications for the treatment of autoimmune diseases by MHC blockade.

Actins↗
PubMed1991

Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction.

By generating two types of transgenic mice we have investigated how extrathymic events can contribute to self tolerance. The major histocompatibility complex class I gene Kb was expressed under the control of the glial fibrillary acidic protein promoter in cells of neuroectodermal origin outside the thymus. These mice were tolerant to Kb. When crossed to transgenic mice expressing a Kb-specific T cell receptor (TCR), clonotype+, CD8+CD4- mature T cells could be detected in normal numbers in the thymus of the double-transgenic mice but were strongly reduced in spleen and lymph nodes in comparison with TCR single-transgenic mice. After isolation of clonotype negative splenic T cells and activation in vitro, reappearance of the clonotype+, CD8+CD4- cells was observed. These results indicate that down-regulation of TCR and CD8 molecules on the antigen-specific T cells is a novel mechanism, by which peripheral tolerance to this antigen can occur.

Animals↗
PubMed1991

Influence of major histocompatibility complex class I and II antigens on survival in colorectal carcinoma.

HLA-A,B,C and HLA-D molecules present antigenic peptides to the antigen-specific receptor of autologous T-lymphocytes. T-cell-mediated host-versus-tumor response might therefore depend on the presence of these molecules on tumor cells, although the absence of HLA-A,B,C determinants on a cell has been shown to increase its susceptibility to lysis by natural killer cells. To investigate whether the presence or absence of HLA-A,B,C and/or HLA-DR in colorectal carcinoma influences relapse rate and time of tumor-related death, 152 patients who underwent putatively curative surgical treatment were surveyed for a maximum of 65 months (mean, 48 months). As determined by immunohistochemistry, aberrant reduction or loss of HLA-A,B,C/beta 2-microglobulin molecules was more frequent in tumors of the proximal colon than of the rectosigmoid (P = 0.032) and in mucinous carcinomas than in nonmucinous ones (P = 0.022). An abnormal induction of the HLA-D-associated invariant chain (Ii) was more frequent in Dukes' A and B than in stage C (P = 0.046). Reduction/loss of HLA-A,B,C/beta 2-microglobulin was correlated with the absence of HLA-DR (P = 0.024) and Ii (P = 0.005). In contrast to the prognostic role of tumor stage and grade, the presence versus the absence of HLA-A,B,C/beta 2-microglobulin and HLA-DR/Ii molecules was not correlated with recurrence rate or survival. We conclude that in spite of an increasing amount of experimental data suggesting the contrary, the status of HLA-A,B,C and HLA-DR expression in colorectal carcinoma seems to be irrelevant in vivo, regarding survival and growth of residual tumor cells after putatively curative resection of the initial tumor burden.

Aged↗
PubMed1991

Antigen presentation of hen egg-white lysozyme but not of ribonuclease A is augmented by the major histocompatibility complex class II-associated invariant chain.

The influence of the class II-associated invariant chain (Ii) on the presentation of the protein antigens hen egg-white lysozyme (HEL) and ribonuclease A (RNase) was investigated. For this purpose the Ii- rat-2 fibroblasts were transfected with I-Ak genes with or without Ii. Transfectants expressing Ii were superior in the presentation of the complete HEL protein to a panel of I-Ak-restricted T hybridomas characterized by distinct specificities for different HEL peptides and by different sensitivities to antigen concentration. There appeared to be a correlation between the antigen-presenting capacity and the amount of Ii, in that transfectants expressing large amounts of Ii were the best antigen presentors. The presentation of synthetic HEL peptides was not influenced by Ii. In contrast to the findings with HEL, the presentation of RNase by the same set of transfectants was clearly independent of Ii. Both antigens, HEL and RNase, required processing in the chloroquine-sensitive compartment. However, only the presentation of HEL but not of RNase could be efficiently blocked by brefeldin A. These data confirm that presentation of HEL depends on de novo synthesized class II molecules, whereas the presentation of RNase seems to be predominantly mediated by a pool of pre-existing class II molecules whose interaction with endocytosed antigen does not depend on Ii. These results suggest different mechanisms for the presentation of HEL and RNase and they raise the possibility that different antigens intersect the class II pathway at distinct intracellular locations.

Animals↗
PubMed1991

Frequency of abnormal expression of HLA-A,B,C and HLA-DR molecules, invariant chain, and LFA-3 (CD58) in colorectal carcinoma and its impact on tumor recurrence.

HLA-A,B,C and HLA-DR molecules are involved in cognate LFA-3 (CD58) in antigen-independent T-cell/target-cell interaction. T-cell-mediated host-versus-tumor response might therefore depend on the presence of both types of molecules on the surface of the target cell. To investigate whether presence or absence of these molecules in colorectal carcinoma influences the recurrence rate, 149 patients who underwent curative surgery were surveyed for a maximum of 65 months (mean, 48 months). As determined by immunohistochemistry, aberrant reduction of HLA-A,B,C determinants was observed in 34.9 and a complete loss in 8.7% of the tumor specimens. An induction of HLA-DR molecules was found in 55.0 and of the HLA-DR-associated invariant chain (Ii) in 81.9%. An abnormal reduction of LFA-3 was detected in 43.6%, while a complete loss of this structure was observed in 6.7%. Reduction/loss of HLA-A,B,C was correlated with reduction/loss of LFA-3 (p = 0.03). In contrast to the prognostic role of tumor stage and grade, the presence vs. absence of all these structures was not correlated with the recurrence rate. We conclude that, although encoded on different chromosomes, an abnormal reduction/loss of HLA-A,B,C and LFA-3 might be the consequence of one transacting down-regulating signal. However, the resulting deviant immunophenotypes do not profoundly influence survival and growth potential of residual tumor cells.

Antibodies, Monoclonal↗
PubMed1991

Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue-specific expression of a foreign MHC class I antigen.

The studies described here reveal a surprising variety of non-deletional manifestations of tolerance (anergy and unresponsiveness) in both the thymus and peripheral lymphoid organs. This can be observed in anti-Kb TCR transgenic mice crossed with normal Kb positive mice, and in TCR mice crossed with transgenic mice expressing Kb in restricted tissues, such as liver, epithelial cells, cells of neuroectodermal origin etc. Thymic induction of unresponsiveness: Transgenic mice were prepared with the a, beta TCR genes from a CD8-dependent and Kb-specific CTL clone. In homozygous H-2b mice clonotype+ cells were found in the thymus but none or few in the periphery, suggesting that deletion occurs in the thymus although lack of migration to the periphery has not been ruled out. In H-2 heterozygous mice (TCR.H-2kxb) deletion was incomplete in the thymus and clonotype+ cells accumulated substantially in the periphery. Most of them had downregulated their CD8 molecules. The clonotype+ cells in both the thymus and periphery were unresponsive to the Kb antigen in vitro, suggesting the induction of anergy in the thymus. The inefficient negative selection in H-hkxb heterozygous mice is probably due to the lower Kb expression in comparison to H-2b homozygous mice. We then further reduced the amount of Kb expression in the thymus by constructing Kb transgenic mice using the 0.8 Kb fragment of the keratin IV promoter. In the thymus expression was only observed on a subset of medullary epithelial cells. When these mice were crossed with the TCR transgenic mice than no deletion was observed in the thymus. However, the clonotype+ CD8+ thymocytes could not respond to Kb in vitro, indicating that they had been rendered anergic in the thymus. These data show that unresponsiveness can be induced in the thymus, that the extent of clonal deletion can vary greatly owing to a change in antigen expression by a factor of two as in H-2 heterozygous versus homozygous mice, and that expression of Kb on a few medullary thymic epithelial cells is sufficient to induce anergy. Peripheral induction of unresponsiveness: To study the consequence of tissue-specific tolerogen expression we have generated transgenic mice expressing Kb exclusively in cells of neuroectodermal origin (GFAP.Kb mice) in the liver (alumin.Kb mice), or in certain epithelial cells outside the thymus (2.4 keratin IV.Kb mice). Consistent with the absence of Kb expression in the thymus there was no deletion of clonotype+ CD8+ cells in the thymus, and the thymocytes were fully functional.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Selective loss of beta 2-microglobulin mRNA in human colon carcinoma.

Expression of MHC class I antigens requires the intracellular assembly of HLA-A,B,C H chains and beta 2-microglobulin (beta 2m). We have investigated the expression of free H chain, beta 2m, and their mRNAs in tissue sections of colon carcinomas that were defective for the native two-chain molecule. In all of these tumors, beta 2m protein and mRNA were found to be completely absent from the neoplastic cells, whereas free H chains and their respective mRNAs were present in abundance in the tumor cell cytoplasm. The selective abrogation of beta 2m expression represents a unique mechanism leading to a complete loss of class I antigen surface expression in vivo.

Carcinoma↗
PubMed1989

Selective loss of HLA-A or HLA-B antigen expression in colon carcinoma.

A panel of colorectal carcinomas has been examined immunohistologically with mAb specific for allodeterminants of HLA-A or HLA-B, and with mAb reactive with HLA-A,B,C framework determinants or beta 2-microglobulin. Out of 85 carcinomas, 5 cases were completely negative for all class I Ag in the tumor cell population. Fifteen cases exhibited a differential expression of HLA-A and HLA-B products in all tumor cells or in a subset. Such tumor cells showed strong staining with monomorphic HLA antibodies but failed to stain with certain allospecific mAb. Negativity of tumor cells was scored only when normal stromal cells within the tumor mass were clearly labeled, indicating expression of the particular allodeterminant(s) in the given tissue. Four carcinomas showed a selective loss of HLA-A2 or a non-A2 HLA-A allospecificity in all tumor cells or a major subset, whereas HLA-B Ag were expressed. Seven cases showed a selective loss of the HLA-Bw6 superspecificity in the tumor cell population; HLA-Bw4 and HLA-A Ag were present. Three cases exhibited a combined loss of HLA-A2 and HLA-Bw6 Ag, with non-A2 HLA-A and HLA-Bw4 Ag being expressed. A further case was HLA-Bw6/Bw4 negative in a major tumor cell subset and HLA-A negative in the complementary minor subset. The results show that a considerable proportion of colorectal carcinomas is heterogeneous with regard to HLA-A and HLA-B expression. The reasons for the appearance of tumor subsets with complete loss of class I Ag or selective loss of only HLA-A or HLA-B Ag are not clear, but it is conceivable that some of them arose because they have escaped immunoselection.

Alleles↗
PubMed1989

Expression of epidermal growth factor receptor in benign and malignant primary tumours of the breast.

Using the monoclonal antibody EGF-R1, normal mammary gland and a series of 213 unselected primary breast tumours were investigated immunohistochemically for expression of epidermal growth factor receptor (EGFR). In normal breast EGFR was expressed in variable patterns in lobular, ductal, and myoepithelial cells. In fibroadenoma, EGFR was detectable in variable numbers of ductal and myoepithelial cells and in stromal fibroblasts. The myoepithelial compartment of 2 cystosarcomas phyllodes also expressed EGFR. Among the 197 carcinomas tested only 20.3% contained EGFR expressing tumour cells which represented a minority in 12.2%, the majority in 2.1%, and the entire neoplastic population in 6.1% of the cases. Again, non-neoplastic ductal remnants often contained EGFR positive myoepithelial and ductal cells whereas stromal fibroblasts expressed EGFR only occasionally. We conclude that in contrast to the normal state, EGFR-expression is a rather rare phenomenon in breast carcinoma cells, positively correlated with a declining grade of differentiation (p less than 0.025) and at least occasionally associated with squamous metaplasia within the tumour, that EGFR expression is not exclusively restricted to cells of the epithelial lineage, and that EGFR may have other functions not related to proliferation, since it is commonly detectable in myoepithelial cells.

Breast↗
PubMed1988

Growth and metastasis of human tumors in nude mice following tumor-cell inoculation into a vascularized polyurethane sponge matrix.

Growth and metastasis of human tumor cells in immunodeficient nude mice were improved when tumor cells were inoculated within a vascularized artificial polyurethane sponge matrix. The sponges had been implanted 7-10 days earlier and were vascularized at the time of cell injection. All cell lines tested, including colon carcinoma-derived lines from primary tumors (HT29, PT3 and PT4) or from liver metastasis (LM3), and a metastatic variant from a melanoma (MeWo-Met) grew in a high percentage (78-94%) of the inoculated sponge grafts. When growth in sponge grafts is compared with growth at a subcutaneous site, the sponge matrix appears to increase tumorigenicity, at least for some cell lines. Regular formation of metastases was observed when cells had been injected into sponges. Most metastases were found in a second sponge graft implanted at a contralateral site, but some were also found at other s.c. sites. In vivo depletion of NK cells by pre-treatment with cyclophosphamide could not further enhance the formation of metastasis. Tumor cells from fresh surgical specimens could be propagated in sponge matrix grafts and subsequently established as cell lines in tissue culture.

Animals↗
PubMed1988

Cooperative effect of interferon-gamma and tumor necrosis factor-alpha on the induction of the class II antigen-associated invariant chain expression.

The regulation of the invariant chain (Ii) expression was studied in the human colon carcinoma cell line HT-29 that constitutively expressed neither Ii nor class II antigens. Upon stimulation of HT-29 cells with a combination of human recombinant tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), expression of mRNA and protein of the invariant chain were induced. In contrast, administration of TNF-alpha or IFN-gamma alone had no effect. A delayed induction of Ii mRNA, which was first detected 10-12 h after stimulation, was observed; this suggests an indirect regulatory mechanism. Stimulation with both IFN-gamma and TNF-alpha led to the co-expression of class II antigens with the invariant chain. In order to study the genetic basis for this stimulation the murine invariant chain gene (800 bp 5' flanking sequences and the structural gene) was transfected into HT-29 cells and transfected cells were tested for the ability to respond to IFN-gamma and TNF-alpha. Simultaneous application of both cytokines had a strong effect on the induction of the murine invariant chain. IFN-gamma alone had no effect and TNF-alpha only marginally stimulates murine invariant chain expression. The transfection experiment indicates that the murine invariant chain gene construct contains the structural elements which are responsible for regulation with IFN-gamma and TNF-alpha. We determined whether the cooperative effect of TNF-alpha and IFN-gamma is also found in vivo. Stimulations of mice were performed with TNF-alpha, IFN-gamma and a combination of both. The immunohistological analysis of kidney tissue sections revealed that TNF-alpha had no effect on Ii and Ia expression. Upon IFN-gamma treatment a minor subset of renal tubules showed staining for Ii, and less prominently also for Ia. However, simultaneous application of both cytokines led a strong induction of both Ii and Ia antigens in renal epithelial cells, thus suggesting that this synergistic effect potentially occurs under physiological conditions.

Animals↗
PubMed1988

Differential expression of HLA-DR, HLA-DP, HLA-DQ and associated invariant chain (Ii) in normal colorectal mucosa, adenoma and carcinoma.

The expression of MHC class II antigens (HLA-DR, HLA-DP and HLA-DQ) and the associated invariant chain (Ii) was studied in epithelial cells of normal colorectal mucosae, colorectal adenomas and carcinomas, using a sensitive immunoperoxidase technique with monoclonal antibodies on frozen sections. In contrast to class II antigens, Ii was detected in some normal mucosae distant from the tumour. In residual non-neoplastic mucosa adjacent to carcinomas, Ii and class II antigens were induced in the order Ii greater than or equal to HLA-DR greater than or equal to HLA-DP greater than or equal to HLA-DQ, the reactions being most pronounced in cases with inflammatory alteration of the crypts. In 22/37 adenomas and 77/123 carcinomas, Ii expression clearly exceeded class II antigen expression. Class II antigens were found in 20/37 adenomas and 62/123 carcinomas, mostly in a non-coordinate manner, following the above order. A detailed analysis of the expression patterns in normal and neoplastic colon epithelial cells revealed a closer association of HLA-DP with HLA-DQ than of HLA-DR with HLA-DP, or HLA-DQ.

Adenoma↗
PubMed1988

Intra- and extrathymic B cells in physiologic and pathologic conditions. Immunohistochemical study on normal thymus and lymphofollicular hyperplasia of the thymus.

Normal thymuses and thymuses with lymphofollicular hyperplasia have been examined immunohistologically using immunoenzymatic single and double labelling methods and a panel of monoclonal antibodies against B lymphocyte differentiation antigens (CD19-, CD20-, CD21-, CD22-, CD23- and CD37ag) and human immunoglobulins (IgM, IgD) for the presence and localisation of B lymphocytes and cells expressing B cell differentiation antigens. The numerous hyperplastic lymph follicles which occur in the pathological condition of lymphofollicular hyperplasia of the thymus were found to originate in the extrathymic compartment of the interlobular septal space. This area was found to be blown up by the growing lymph follicles with exactly the same cellular composition as their counterparts in the peripheral lymphatic tissue. Some of the B lymphocytes expressing the immunophenotype of follicular mantle zone lymphocytes which were detected in the thymic medulla probably infiltrated through discontinuities of the border between the perivascular space and the thymic medulla. Apart from this primarily extrathymic B cell compartment, B lymphocytes and cells expressing B cell antigens were found within the thymus medulla of normal control thymuses of different ages from fetal to adult life. These cells were detected as a small subpopulation in normal fetal, juvenile and adult thymuses. Morphologically they could be subdivided into small, round lymphoid cells accounting for less than 1% of medullary lymphoid cells, and into a larger variant, asteroidally shaped because of short cytoplasmic processes. These asteroid cells were even more infrequent than the lymphoid variant. Immunophenotype (CD19ag+, CD20ag+, CD22ag+, CD37ag+, IgM+, IgD+) and morphology of the first cell type led to the conclusion that the lymphoid cells were in fact B lymphocytes. They were scattered throughout the medulla of fetal and juvenile and adult thymuses alike. The second, the asteroid cell type, constantly expressed CD20ag and inconstantly IgM, CD22ag and CD37ag; furthermore, CD23ag was detected in a subset of the asteroid cells either restricted to the perinuclear zone or expressed in the entire cytoplasma and on the plasma membrane. The asteroid cells were located in the corticomedullary region of the fetal thymuses but were randomly distributed with a tendency to Hassall's corpuscles in juvenile and adult thymuses. They often formed rosettes with non-B lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1988

Thymic medullary cells expressing B lymphocyte antigens.

A small subpopulation of human thymic medullary cells was found to express B cell-restricted and -associated antigens in various combinations. The cells were detected in fetal, juvenile, and adult thymi using indirect immunoenzymatic methods and monoclonal antibodies (MoAbs). Morphologically, they could be subdivided into small, round lymphoid cells, accounting for less than 1% of medullary lymphoid cells, and into a larger variant, even more infrequent in number and asteroid in shape because of short cytoplasmic processes. Immunophenotype (CD19+, CD20+, CD22+, CD37+, IgM+, IgD+) and morphology of the first cell type led to the conclusion that the lymphoid cells were B lymphocytes. The second, asteroid cell type constantly expressed CD20 and inconstantly expressed IgM, CD19, CD22, and CD37; they were often found to form rosettes with non-B lymphocytes. It can be concluded that a small number of B cells and asteroid cells of still uncertain origin, but expressing B cell-restricted antigens, are constitutive elements of the fetal and adult thymic medulla. It can be hypothesized that the asteroid cell might represent a novel type of thymic accessory cell and that the rosetting of non-B lymphocytes around this asteroid cell might simulate or in fact be the earliest B cell interaction of maturing T cells.

Adolescent↗
PubMed1988

Reduction or loss of HLA-A,B,C antigens in colorectal carcinoma appears not to influence survival.

Primary colorectal carcinomas of an unselected group of 159 patients 126 of whom could be curatively resected were examined for the expression of MHC class I antigens with monoclonal antibody W6/32 directed against a non-polymorphic determinant of HLA-A,B,C heavy chain. One hundred and nine (68.6%) were found to express HLA-A,B,C antigens in normal quantities, 33 (20.8%) showed a substantial reduction in expression, while 17 (10%) lacked these antigens either completely or incompletely. The loss of HLA-A,B,C was inversely correlated with the degree of differentiation. The tendency of mucinous carcinomas to lack class I antigens was statistically not significant. Tumours with distant metastatic spread at the time of operation tended to be normal with respect to HLA-A,B,C expression. Within the curatively resected group, poor differentiation and mucus production were risk factors for survival as could be shown by life table analysis after a maximum follow-up of 39 months. In contrast, the mode of HLA-A,B,C expression of the primary tumour did not influence survival within this time of observation. We conclude that in spite of increasing experimental data suggesting the contrary, the presence or absence of MHC class I antigens does not seem to profoundly modify tumour biology, at least in human colorectal carcinoma.

Adenocarcinoma↗
PubMed1988

Nonimmune human cells can express MHC class II antigens in the absence of invariant chain--an immunohistological study on normal and chronically inflamed small intestine.

The expression of HLA-DR, HLA-DP and HLA-DQ antigens and of the associated invariant chain (Ii) was studied immunohistologically in sessile cells of normal ileum and ileum affected by Crohn's disease which was taken as a model for chronic inflammation. Corresponding to the local inflammatory cell density, a considerable neo-expression of MHC class II antigens and Ii was observed in epithelial cells, vascular endothelial cells, and Schwann cells of the enteric nerve plexus. While HLA-DP and HLA-DQ antigens were undetectable in sessile cells of normal ileum, class II antigens expression in ileitis followed the order HLA-DR greater than or equal to HLA-DP greater than or equal to HLA-DQ. In various cell types a differential expression of Ii and class II antigens was noted. In normal crypt enterocytes and in arterial endothelial cells of inflamed ileum, Ii was found in the absence of class II antigens. On the other hand, most Schwann cells and internodal nerve strands of the submucous and myenteric plexus exhibited HLA-DR (-DP, -DQ) antigens in the absence of detectable Ii. Moreover, HLA-DR+ endothelial cells in normal tissue specimens were Ii-, and in inflamed intestine HLA-DR expression of venous/venular and capillary endothelium greatly exceeded Ii expression. The observation of both Ii+/HLA-DR- and Ii-/HLA-DR+ (HLA-DP+, HLA-DQ+) cells questions the previously assumed close association of Ii and class II antigen expression.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1988

Lack of vimentin occurring during the intrafollicular stages of B cell development characterizes follicular center cell lymphomas.

Reactive germinal-center B cells completely lack vimentin. This observation made by using monoclonal vimentin antibody V9 and a sensitive immunoperoxidase technique led to the investigation of vimentin expression in an unselected series of 73 immunohistochemically proven B cell lymphomas. While small lymphocytic lymphomas regularly expressed vimentin, the neoplastic population of mixed, small and large, and large cell lymphomas often contained various proportions of vimentin-negative tumor cells or failed to express it at all. Against the background of the Lukes-Collins classification and the Kiel classification, both defining and subdividing follicular center-cell lymphomas, there were statistically highly significant correlations between the absence of vimentin and the histology, suggesting a germinal center origin. Our data suggest that loss of vimentin expression is indicative of the transient, follicular center-cell stage of normal and malignant B lymphocytic transformation. The complete absence of vimentin within the neoplastic population of all Burkitt's lymphoma cases examined may serve as an argument for its follicular center stage of differentiation, as was asserted by Lukes and Collins.

B-Lymphocytes↗