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Biomedical subjects

G H Boerrigter

Publications and source records attributed to G H Boerrigter.

13 recordsLinked to original sources
PubMed1988

Hapten-specific antibodies in allergic contact dermatitis in the guinea pig.

A guinea pig model was used to investigate the potential role of hapten-specific antibodies in allergic contact dermatitis. Hapten-specific antibodies of both the IgG1, IgG2 and IgM (sub)classes could be readily detected by ELISA in sera obtained after single or repeated exposure to the allergens 2,4-dinitrochlorobenzene (DNCB) or 4-ethoxymethylene-2-phenyloxazolone. Experiments in which animals were strongly boostered with Freund's complete adjuvant support previous reports that hapten-specific antibodies are able to transfer contact skin reactions with a delayed time course into naive recipients. In contrast, epicutaneous sensitization procedures never allowed transfer of such reactivity. Upon transfer of immune sera to previously sensitized animals, existing allergic contact dermatitis was unaffected, except for a distinct suppression of induration, but not erythema, in the DNCB system. In actively sensitized animals, antibody-related suppression of induration was never observed. Hapten-specific hyposensitivity, as induced by repeated epicutaneous exposure, was also not related to circulating antibody levels. Our findings do not support the view that hapten-specific antibodies should be reconsidered as playing a potentially important role in allergic contact dermatitis.

Animals↗
PubMed1987

Local and systemic desensitization induced by repeated epicutaneous hapten application.

Frequent skin exposure of guinea pigs to the contact sensitizing agents dinitrochlorobenzene or 4-ethoxymethylene-2-phenyloxazolone induced both systemic hyposensitization and local unresponsiveness within 8 weeks. Both phenomena were hapten-specific. Decreased systemic reactivity in repeatedly painted guinea pigs is probably not due to receptor blockade or the development of hapten-specific antibodies, but rather to transient sequestration of hapten-specific effector cells within lymph nodes draining the site of hapten exposure. After discontinuation of allergen exposure, effector cells return into the circulation, as indicated by a reversal of systemic hyporesponsiveness within 5 weeks. The persistence of a cellular infiltrate at the site of repeated application and the hapten-specific unresponsiveness at this site suggest that suppressor cells play a role in local unresponsiveness. Upon discontinuation of allergen exposure, local unresponsiveness rapidly dissolves (within one week). Since the circulation is still depleted of effector cells, residual hyporesponsiveness may persist for longer periods.

Administration, Topical↗
PubMed1986

Intradermal administration of 4-hydroperoxy-cyclophosphamide during contact sensitization potentiates effector T cell responsiveness in draining lymph nodes.

4-Hydroperoxy-cyclophosphamide (4-HPCY) is an in vitro active form of cyclophosphamide. In a previous study, using an in vivo contact sensitivity model in the guinea pig, we demonstrated that intradermal injection of small amounts (50-200 micrograms) of 4-HPCY at the sensitization site resulted in strong potentiation of contact hypersensitivity (Boerrigter and Scheper, 1984). It was postulated that 4-HPCY induces a local decrease of feedback control within the draining antigenically stimulated lymph nodes. The present data are in support of this view: Lymph node hyperplasia induced by contact sensitization (to dinitrochlorobenzene or oxazolone) was further enhanced by 4-HPCY treatment. The paracortical area was preferentially enlarged. 4-HPCY-treated lymph nodes showed an augmentation of hapten-specific T effector cell function as determined in transfer experiments. The response of such lymph node-derived cells to the T cell mitogen PHA was enhanced. Although 4-HPCY treatment resulted simultaneously in a decrease in responsiveness of draining lymph node-derived cells to the B cell mitogen lipopolysaccharide, anti-hapten antibody production was not affected. The present study demonstrates that important similarities exist between the effects of local 4-HPCY treatment and systemic cyclophosphamide pretreatment on the immune response. As systemic treatment with a high dose of cyclophosphamide is known to have serious side effects, the present local protocol provides a new attractive and versatile strategy for T cell immunopotentiation.

Animals↗
PubMed1986

Chemosensitivity of human head and neck cancer xenografts in the clonogenic assay and in nude mice.

The potential use of human head and neck (H & N) tumours, growing in athymic nude mice, for preclinical assessment of cytostatic drug sensitivity in a soft agar cloning system was examined. Of 20 H & N tumour xenografts, obtained from 6 different xenograft lines, 17 demonstrated sufficient colony growth to evaluate in vitro drug sensitivity. Moreover, all xenografts provided enough cells to test 8 cytostatic drugs at 3 concentrations each. A dose-dependent inhibition of colony growth was obtained with all drugs tested, except methotrexate. Tumours were considered sensitive when the drug concentration required to inhibit colony formation by 50%, was less than 1/10 of the peak plasma concentration in patients. All H & N tumour lines were resistant to cisplatin, doxorubicin, hydroxyurea, mafosfamide (an in vitro active analogue of cyclophosphamide) and methotrexate. Bleomycin was active in 1/6 and 5-fluorouracil in 6/6 of the H & N tumour lines tested. In 32 cases the in vitro data of the H & N tumour lines and a chemosensitive rat rhabdomyosarcoma were compared directly with in vivo results obtained in nude mice. The clonogenic assay correctly predicted sensitivity in 4/6 (66.7%) and resistance in 21/26 (80.8%) of the cases. A lack of correlation was noted for methotrexate, 5-fluorouracil and cyclophosphamide. In vitro culture of human H & N xenografts may provide a means for a rapid and large scale screening to identify new drugs active against H & N malignancies. In addition the clonogenic assay may help to select drugs for subsequent testing in the nude mouse xenograft model. The lack of correlation for some drugs in the present study indicates that there are some limitations in the use of xenograft tumour material for in vitro testing of new drugs.

Animals↗
PubMed1985

Successful in vitro growth of human head and neck cancer after transplantation in nude mice.

Head and neck tumours from 14 different lines growing in athymic nude mice were cultured in a soft agar cloning assay. Eleven lines (79%) demonstrated growth with more than 100 colonies per 3 X 10(5) cells plated. These results are much more favourable than those obtained with head and neck tumours taken directly from the patient. It is suggested that the combination of the athymic nude mouse xenograft model with the clonogenic assay could serve as a new screening model for chemotherapeutic agents against head and neck cancer.

Animals↗
PubMed1984

Evaluation of various cytostatic drugs as local immunotherapeutic agents.

The cytostatic drugs methotrexate, 5-fluorouracil, adriamycin, vincristin, cisplatinum, VP-16 and the newly synthesized, stabile cyclophosphamide-derivative Z-7557, were screened for possible immunopotentiating effects in local chemotherapy. With an in vivo contact sensitivity model in guinea pigs, low dosages of the drugs were introduced into antigenically stimulated lymph nodes by intradermal injections following sensitization. Marked till strong potentiation of T-cell function, as measured by the development of contact hypersensitivity, was observed with all drugs tested, except for methotrexate and 5-fluorouracil. With a similar local chemotherapeutic protocol in the guinea pig line 10 hepatocellular carcinoma-model, these latter drugs have been reported earlier to be exceptional in failing to induce tumor regression and tumor immunity. Our present results suggest that local chemotherapy of malignancies not only may reduce local tumor load, but also may affect distant metastases by facilitating the development of tumor-specific immunity.

Adjuvants, Immunologic↗
PubMed1984

Induction of contact sensitivity to a broad variety of allergens with haptenized macrophages.

Using guinea pigs an analysis could be made of various aspects of contact sensitivity (CS) induced by subcutaneous injection of syngeneic haptenized macrophages (oil-induced peritoneal exudate cells, PEC) as compared to epicutaneous sensitization. Very little PEC-bound hapten (dinitrochlorobenzene, or oxazolone) is needed for optimum sensitization. Nevertheless, both sensitization methods induce a state of CS that may last for over 6 months, give rise to hapten-specific antibodies with a similar isotype distribution, and show susceptibility to cyclophosphamide pretreatment. In addition, time courses and microscopic appearance of skin test reactions after either way of sensitization are identical. CS to a broad variety of physicochemically different antigens, including nickel, penicillin, and acrylates, is readily induced by syngeneic PEC, haptenized following a standardized procedure. As Freund's complete adjuvant is known to cause serious side effects like ulceration and long-lasting granuloma formation, immunization with haptenized PEC should now be considered as a clean and effective alternative in experimental CS studies.

Allergens↗
PubMed1984

Local administration of cytostatic drug 4-hydroperoxy-cyclophosphamide (4-HPCY) facilitates cell-mediated immune reactions.

4-Hydroperoxy-cyclophosphamide (4-HPCY) is a cyclophosphamide (CY) derivative that, unlike CY, does not need liver conversion for its action. This new drug has been recently described to preferentially eliminate suppressor B and T lymphocytes in vitro in both mice and man. Using an in vivo contact sensitivity model in the guinea-pig, we introduced 4-HPCY into antigenically stimulated lymph nodes by local intradermal injection following sensitization. Strong potentiation of contact sensitization was achieved by local administration of doses higher than 50 micrograms 4-HPCY daily on 4 days subsequent to sensitization. Contact hypersensitivity was found to be enhanced for at least 6 weeks. In addition it could be demonstrated that local administration of 4-HPCY not only enhanced the development of delayed hypersensitivity in normal animals, but also facilitated the reversal of previously induced immunological tolerance. The applicability of this new strategy for potentiation of effector T cell function, especially with respect to the treatment of malignancies, is stressed.

Adjuvants, Immunologic↗
PubMed1983

Direct measurement of in vitro antibody production using an enzyme-linked immunosorbent assay.

A rapid and sensitive enzyme-linked immunoassay is described for quantitation of the secretion of cellular products during short-term (1-20 h) culture in vitro. The method is based on culture of cells, serially diluted in antigen or antibody-coated polystyrene microtitre wells. The wide applicability of this method for measurement of anti-hapten antibody, immunoglobulin and lymphokine production is stressed.

Animals↗
PubMed1983

Induction of immunological memory in the skin. Role of local T cell retention.

Using an experimental contact sensitivity model in guinea-pigs, evidence is presented that hapten (DNCB or oxazolone) specific T lymphocytes may persist for several months in previous sites of inflammation. Immunological memory, revealed by accelerated contact skin reactions upon retesting with the hapten, was limited to the original contact skin reaction sites. This 'local skin memory' to DNCB or oxazolone could be induced in both specific and non-specific skin inflammatory reactions, provided the animals had been sensitized to the hapten not longer than 2 weeks before. In animals which had been sensitized more than 1 month earlier, local skin memory could be induced if the animals received a booster application of hapten shortly (0-2 days) before primary skin testing. From these results we conclude that recently activated T cells may enter inflammatory sites non-specifically, producing specific local immunological memory. This memory may last several months. Accumulation of hapten specific T cells at inflammatory sites may be important in retest reactivity, in flare-up reactivity and in chronic inflammation.

Animals↗
PubMed1978

Interference of simultaneous skin tests in delayed hypersensitivity.

The interference of two simultaneous skin test reactions of intermediate strength has been studied in the guinea-pig, using four different antigens, i.e. ovalbumin, horse cytochrome c, PPD and oxazolone. Skin test reactions were evaluated at 4, 24 and 48 h by measuring three parameters: increase in skin thickness, diameter of erythema and intensity of erythema. When an Arthus reaction was elicited simultaneously with a delayed hypersensitivity (DH) reaction, no effect on the DH reaction was observed. When two simultaneous DH reactions were elicited with different antigens, the risk of interference appeared to be rather small. When, however, the same antigen was used for both skin tests, suppression of at least one parameter of a DH-reaction was found in almost all experiments. Suppression of one skin test by another one could not be reduced by introducing a large distance between the two skin tests. As complete inhibition of either of the parameters never occurred, multiple skin testing may allow one to obtain a qualitative impression of the state of delayed hypersensitivity; when, however, reliable quantitative data are needed, the performance of more than one skin test at a time should be avoided.

Animals↗
PubMedDate not supplied

Lack of effect of methotrexate on human head and neck tumours transplanted in athymic nude mice.

Human head and neck tumour tissues derived from 16 different patients were transplanted in athymic nude mice. Treatment of tumour-bearing animals with methotrexate had little or no effect on the doubling time of the xenografts. Included were three tumour lines derived from patients in whom methotrexate did demonstrate antitumour activity. These results are also in contrast to clinical experience with methotrexate, showing remissions in 50% of patients with head and neck cancer. It is unlikely that this lack of effect of methotrexate is attributed to a difference in drug pharmacokinetics between man and nude mouse, since a xenografted rat tumour was found to be sensitive. With regard to possible resistance mechanisms underlying methotrexate inactivity, we found no evidence of increased dihydrofolate reductase activity in the methotrexate-insensitive human xenografts. It is possible that in this model a selection occurs favouring the outgrowth of a resistant subpopulation of tumour cells.

Animals↗