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Biomedical subjects

J Knop

Publications and source records attributed to J Knop.

At least 37 records · Page 2Linked to original sources
PubMed2001

A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection.

Dendritic cells (DCs) elicit potent anti-tumoral T-cell responses in vitro and in vivo. However, different types of DC have yet to be compared for their capacity to induce anti-tumor responses in vivo at different developmental stages. Herein, we correlated the efficiencies of different types of monocyte-derived DC as vaccines on the resulting anti-tumor immune responses in vivo. Immature and mature DCs were separately pulsed with a peptide derived from tyrosinase, MelanA/MART-1 or MAGE-1 and a recall antigen. Both DC populations were injected every 2 weeks in different lymph nodes of the same patient. Immune responses were monitored before, during and after vaccination. Mature DCs induced increased recall antigen-specific CD4(+) T-cell responses in 7/8 patients, while immature DCs did so in only 3/8. Expansion of peptide-specific IFN-gamma-producing CD8(+) T cells was observed in 5/7 patients vaccinated with mature DCs but in only 1/7 using immature DCs. However, these functional data did not correlate with the tetramer staining. Herein, immature DCs also showed expansion of peptide-specific T cells. In 2/4 patients vaccinated with mature DCs, we observed induction of peptide-specific cytotoxic T cells, as monitored by chromium-release assays, whereas immature DCs failed to induce peptide-specific cytotoxic T cells in the same patients. Instead, FCS-cultured immature DCs induced FCS-specific IgE responses in 1 patient. Our data demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient. Thus, our data define FCS-free cultured mature DCs as superior inducers of T-cell responses in melanoma patients.

Adjuvants, Immunologic↗
PubMed2001

Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood.

A subpopulation of peripheral human CD4(+)CD25(+) T cells that expresses CD45RO, histocompatibility leukocyte antigen DR, and intracellular cytotoxic T lymphocyte-associated antigen (CTLA) 4 does not expand after stimulation and markedly suppresses the expansion of conventional T cells in a contact-dependent manner. After activation, CD4(+)CD25(+) T cells express CTLA-4 on the surface detectable for several weeks. These cells show a G1/G0 cell cycle arrest and no production of interleukin (IL)-2, IL-4, or interferon (IFN)-gamma on either protein or mRNA levels. The anergic state of CD4(+)CD25(+) T cells is not reversible by the addition of anti-CD28, anti-CTLA-4, anti-transforming growth factor beta, or anti-IL-10 antibody. However, the refractory state of CD4(+)CD25(+) T cells was partially reversible by the addition of IL-2 or IL-4. These data demonstrate that human blood contains a resident T cell population with potent regulatory properties.

Abatacept↗
PubMed2001

[Follicular mycosis fungoides (FMF): a rare disease].

Follicular mycosis Fungoides (FMF) was first described in 1924. Since the first description, 22 patients with this special form of mycosis fungoides have been published. Clinical features include epidermal cysts as well as follicular papules, nodules and hyperkeratoses. FMF can be confused with acneiform dermatoses. In most cases, infiltrated plaques typical for cutaneous T cell lymphoma are also present. Histology shows a monomorphic CD4+ T cell infiltrate. Treatment and prognosis are similar of those of classical mycosis fungoides. We present one patient with FMF and review the literature of all published cases.

Acitretin↗
PubMed2001

Adenovirus-transduced dendritic cells stimulate cellular immunity to melanoma via a CD4(+) T cell-dependent mechanism.

We previously showed that genetic immunization of C57BL/6 mice with recombinant adenovirus encoding human TRP2 (Ad-hTRP2) was able to circumvent tolerance and induce cellular and humoral immune responses to murine TRP2 associated with protection against metastatic growth of B16 melanoma. In the present study we compared delivery of Ad-hTRP2 with cultured dendritic cells (DC) and direct injections of Ad-hTRP2. We show that application of Ad-hTRP2 with cultured DC enhanced protective immunity to B16 melanoma cells. Most importantly, delivery of recombinant adenovirus with DC alters the character of the immune response resulting in preferential stimulation of strong cellular immunity in the absence of significant humoral immunity to the encoded antigen. Adoptive transfer of lymphocytes from mice immunized with Ad-hTRP2-transduced DC confirmed that cellular components of the immune response were responsible for rejection of B16 melanoma. The protective efficacy of Ad-hTRP2-transduced DC clearly depended on the presence of CD4(+) T helper cells. Furthermore, AD-hTRP2-transduced DC, but not direct injection of Ad-hTRP2, were effective in the presence of neutralizing anti-adenoviral antibodies. These preclinical studies demonstrate the superiority of melanoma vaccines consisting of cultured DC transduced with recombinant adenoviruses encoding melanoma antigens.

Adenoviridae↗
PubMed2001

SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis.

BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.

Adolescent↗
PubMed2001

Inhibition of human allergic T-cell responses by IL-10-treated dendritic cells: differences from hydrocortisone-treated dendritic cells.

BACKGROUND: Dendritic cells (DCs) are able to induce human allergic T(H)1 responses as well as T(H)2 responses. OBJECTIVE: In this study, we examined the effect of antiinflammatory agents such as IL-10 and hydrocortisone (HC) on the accessory function of DCs and the resulting T-cell response, especially that of T(H)2 cells. METHODS: Naive and memory CD4(+) T cells from atopic donors were stimulated with autologous allergen-pulsed DCs generated from CD14(+) monocytes by culture with GM-CSF/IL-4 and fully matured with IL-1 beta, TNF-alpha, and PGE(2) in the presence or absence of IL-10 or HC. RESULTS: IL-10-treated DCs and, to a lesser extent, HC-treated DCs showed a decreased expression of MHC II molecules, the costimulatory molecule CD86, and the DC-specific marker CD83, as well as a strongly reduced IL-12 secretion. Consequently, T-cell proliferation was reduced after stimulation with IL-10- or HC-treated DCs alike. However, pretreatment of DCs with IL-10 inhibited the production of T(H)1 and T(H)2 cytokines by T cells, whereas HC-treated DCs inhibited production of IFN-gamma but induced an increased release of IL-4 and no change in IL-5. Both effects were long-lasting; cytokine production remained low (which was due not to enhanced apoptosis but to functional hyporesponsiveness) or even increased after restimulation with fully matured DCs. CONCLUSION: These data indicate that IL-10- or HC-treated DCs differ in their ability to influence human allergic T-cell responses. This has major implications for therapeutic strategies aiming at the downregulation of proallergic T(H)2 responses.

Allergens↗
PubMed2001

The role of interleukin 10 in the regulation of allergic immune responses.

Several clinical studies and animal models have shown that Th2 lymphocytes play a key role in the pathophysiology of IgE-mediated allergic immune responses like allergic rhinitis and asthma or venom anaphylaxis. Classical specific immunotherapy (SIT) that has been proven to be clinically effective can serve as a role model for immunological changes that are associated with amelioration of allergic diseases. During SIT, the Th2-dominated immune response is modified towards a Th1 response leading to a decline in allergen-specific IgE and an increase in allergen-specific IgG production. Most importantly, however, production of the immunosuppressive/-regulatory cytokine interleukin 10 (IL-10) is also induced leading to T cell tolerance and prevention of tissue inflammation. In this article the role of IL-10-producing T cells in the regulation of allergic immune responses will be discussed.

Clonal Anergy↗
PubMed2000

Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.

The functional properties of dendritic cells (DCs) are strictly dependent on their maturational state. To analyze the influence of the maturational state of DCs on priming and differentiation of T cells, immature CD83(-) and mature CD83(+) human DCs were used for stimulation of naive, allogeneic CD4(+) T cells. Repetitive stimulation with mature DCs resulted in a strong expansion of alloreactive T cells and the exclusive development of T helper type 1 (Th1) cells. In contrast, after repetitive stimulation with immature DCs the alloreactive T cells showed an irreversibly inhibited proliferation that could not be restored by restimulation with mature DCs or peripheral blood mononuclear cells, or by the addition of interleukin (IL)-2. Only stimulation of T cells with mature DCs resulted in an upregulation of CD154, CD69, and CD70, whereas T cells activated with immature DCs showed an early upregulation of the negative regulator cytotoxic T lymphocyte-associated molecule 4 (CTLA-4). These T cells lost their ability to produce interferon gamma, IL-2, or IL-4 after several stimulations with immature DCs and differentiated into nonproliferating, IL-10-producing T cells. Furthermore, in coculture experiments these T cells inhibited the antigen-driven proliferation of Th1 cells in a contact- and dose-dependent, but antigen-nonspecific manner. These data show that immature and mature DCs induce different types of T cell responses: inflammatory Th1 cells are induced by mature DCs, and IL-10-producing T cell regulatory 1-like cells by immature DCs.

Antigens↗
PubMed2000

Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived dendritic cells.

Dendritic cell (DC) vaccination, albeit still in an early stage, is a promising strategy to induce immunity to cancer. We explored whether DC can expand Ag-specific CD8+ T cells even in far-advanced stage IV melanoma patients. We found that three to five biweekly vaccinations of mature, monocyte-derived DC (three vaccinations of 6 x 106 s.c. followed by two i.v. ones of 6 and 12 x 106, respectively) pulsed with Mage-3A2.1 tumor and influenza matrix A2. 1-positive control peptides as well as the recall Ag tetanus toxoid (in three of eight patients) generated in all eight patients Ag-specific effector CD8+ T cells that were detectable in blood directly ex vivo. This is the first time that active, melanoma peptide-specific, IFN-gamma-producing, effector CD8+ T cells have been reliably observed in patients vaccinated with melanoma Ags. Therefore, our DC vaccination strategy performs an adjuvant role and encourages further optimization of this new immunization approach.

Antigens, Neoplasm↗
PubMed2000

High dose inhalation interleukin-2 therapy for lung metastases in patients with malignant melanoma.

BACKGROUND: The lungs are a frequent site of metastasis in patients with melanoma, and this may cause respiratory problems in the terminal phase of the illness. Inhalation interleukin (IL)-2 therapy to the lung has been piloted and appears to be well tolerated. METHODS: Twenty-seven patients were treated with single agent dacarbazine and concurrent high dose inhalation IL-2 36 million IU per day). The patients previously had progressed on chemotherapy, predominately dacarbazine-based regimens. Patients included those with American Joint Committee on Cancer Stage IV melanoma, predominately those with lung metastases, but patients with extrapulmonary metastases also were allowed on the study. RESULTS: Five of the 27 patients experienced a complete pulmonary remission. Eight patients achieved a partial pulmonary remission, and 5 patients experienced stabilization of their disease. Eight patients developed pulmonary metastases. One patient was not evaluable. Four of the five patients who achieved a complete response and seven of the eight patients who achieved a partial response previously were treated with dacarbazine and progressed. There were no responses in extrapulmonary metastases. Side effects of treatment were minimal. The complete responses all were durable with a follow-up of 12 months, whereas patients with partial responses and stable disease progressed when IL-2 was discontinued. CONCLUSIONS: Inhalation therapy with IL-2 for pulmonary metastases from melanoma appears to be safe. The current preliminary study suggests efficacy although concurrent chemotherapy was given, thus confounding results to some extent. Therefore, these results need to be reproduced without concomitant chemotherapy. In addition, a strategy comprised of therapy with IL-2 inhalation until disease progression may prolong responses.

Administration, Inhalation↗
PubMed2000

Genetic immunization of mice with human tyrosinase-related protein 2: implications for the immunotherapy of melanoma.

The melanosomal protein TRP2 expressed by melanocytes and most melanoma cells is an attractive, clinically relevant model antigen for the experimental development of melanoma immunotherapy in mice. A peptide shared by murine and human TRP2 can be recognized by melanoma-reactive CTL in C57BL/6 mice, as well as in human melanoma patients. Previous experiments demonstrated that gene gun immunization of mice with plasmid DNA encoding autologous murine TRP2 was unable to induce protective immunity against B16 melanoma cells naturally expressing TRP2. In the present study, we investigated whether the use of cDNA encoding xenogeneic human TRP2, which is highly homologous to murine TRP2, would be more effective. Genetic immunization of mice with human TRP2 resulted in coat depigmentation as a sign of autoimmune-mediated destruction of melanocytes and provided significant protection against metastatic growth of B16 melanoma Induction of protective immunity was associated with TRP2-reactive antibodies and CD8+ T cells. Furthermore, immunization with recombinant adenovirus was more effective than immunization with plasmid DNA using the gene gun. Our results provide new insights for the development of antigen-specific immunotherapy of melanoma.

Adenoviridae↗
PubMed2000

[Calciphylaxis: ischemic tissue necrosis in chronic renal failure. Case report and review of the literature].

Calciphylaxis is a rare but potentially life-threatening complication in chronic renal failure. It is characterized by ischemic tissue necrosis primarily of the skin. The typical histopathologic finding is microvascular calcification with endovascular fibrosis. Patients typically present with violaceous, mottled and painful lesions which tend to progress to non-healing ulcers and necrosis. Most frequently the lower extremities are involved in a symmetric fashion but the trunk may also be affected. Sepsis from superinfection of the lesions accounts for the high mortality of this disease which is of importance for dermatologists and nephrologists alike. 61-year-old female patient developed lesions of calciphylaxis on both calves two years after beginning hemodialysis to treat renal failure due to diabetic glomerulosclerosis. We discuss aspects of the pathogenesis of calciphylaxis, as well as diagnosis, treatment and means of prevention, and review the current literature.

Biopsy↗
PubMed2000

[Successful management of systemic lupus erythematosus with IgM enriched immunoglobulins].

Systemic lupus erythematosus is a potentially life-threatening disease. Even the use of potent immunosuppressive drugs often barely controls the disease. In addition, treatment-related side effects are common due to the high doses of immunosuppressive drugs necessary. We report on two cases of acutely exacerbated systemic lupus erythematosus which were difficult to control with prednisone and cyclophosphamide. Both patients were additionally treated with IgM-enriched preparations of intravenous immunoglobulins. In both cases, the doses of the immunosuppressive drugs used could be significantly reduced. After nine treatment cycles, patients remained disease-free for a follow-up period of one year with only minimal immunosuppressive therapy. Our observation shows that IgM-enriched immunoglobulins can be used for therapy of systemic lupus erythematosus.

Adult↗
PubMed2000

[Stabilizing the course of patients with stage IV advanced malignant melanoma by trofosfamide treatment].

BACKGROUND AND OBJECTIVE: Stage IV melanoma patients with progressive disease are a therapeutic challenge for every dermatologist. We wondered whether a mild oral chemotherapy with trofosfamide would ameliorate disease progression in these patients. PATIENTS/METHODS: 40 patients with melanoma (stage IV disease) were treated with 100 mg/day of trofosfamide for 6 months. All patients showed a progressive disease prior to this intervention. RESULTS: One patient experienced a partial remission, 25 patients showed a stable disease. Only 11 patients were progressive under trofosfamide treatment. 7 patients died during the study period. CONCLUSIONS: Therapy with trofosfamide seems to ameliorate disease progression in stage IV patients.

Administration, Oral↗
PubMed2000

Induction of tumor peptide-specific cytotoxic T cells under serum-free conditions by mature human dendritic cells.

Tumor vaccination strategies using antigen-pulsed dendritic cells (DC) are currently under development. We established an in vitro system using cultured DC from HLA-typed volunteers for the induction of tumor peptide-specific CD8+ T cells. The strength and specificity of the resulting CTL responses were investigated. For stimulation of syngeneic CD8+ T cells two well-defined DC populations were generated: CD1a+ immature DC cultured in the presence of GM-CSF and IL-4 and mature CD83+ DC generated by additional stimulation with a cytokine cocktail. Stimulations were performed under serum-free conditions and in the absence of exogenous cytokines. Analysis of T cell responses showed that mature DC, but not immature DC, were able to induce the expansion of syngeneic tumor peptide-specific CD8+ T cells. Priming of CD8+ T cells with peptide-pulsed mature DC rapidly increased the frequency of antigen-specific T cells (ELISPOT technique). T cells induced by mature DC showed strong antigen-specific cytotoxicity in 51Cr-release assays whereas no antigen-specific cytotoxicity was detectable in CTL generated by immature DC. These data show that terminally differentiated mature DC are necessary for the induction of tumor antigen-specific CTL responses.

Antigens, CD↗
PubMed2000

Induction of dendritic cell maturation and modulation of dendritic cell-induced immune responses by prostaglandins.

Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system. In this study we investigated the effects of various prostaglandins (PG) on the stimulatory capacity of DC. DC were generated from peripheral progenitor cells in the presence of IL-4 and GM-CSF and stimulated with IL-1, IL-6 and TNF-alpha on day 7. Simultaneously, PG (PGD(2), PGE(1), PGE(2), PGF(2 alpha), PGI(2)) were added at various concentrations (10(-5) to 10(-9) M) on day 7. In all experiments, PGE(2) had the most potent influence on the maturation of the DC, followed by other PG in the order PGE(1) > PGD(2) > PGF(2 alpha) > PGI(2). In addition, the expression of the surface molecules CD40, CD54, CD58, CD80, CD83, CD86 and the MHC class II molecules was upregulated after stimulation with PG. Analysis of DC supernatants after treatment with PG demonstrated significantly higher amounts of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha, and IL-12. Addition of PG to DC induced a markedly enhanced proliferation of both naive and activated CD4(+) and CD8(+) T cells in alloantigen-induced MLR assays. Assessment of coculture supernatants after restimulation revealed significantly higher amounts of the Th1-cytokines IL-2 and IFN-gamma and only minimal amounts of IL-4 compared to control cells. No production of IL-10 was observed. The effects of PG on the maturation of DC and enhanced T-cell proliferation could be mimicked by db-cAMP and forskolin, indicating that they were due to elevated cAMP levels. Collectively, our data show that members of the PG family promote the differentiation of DC and enhance their capacity to induce a Th1 immune response.

Antigens, CD↗
PubMed2000

CD83+ human dendritic cells transfected with tumor peptide cDNA by electroporation induce specific T-cell responses: A potential tool for gene immunotherapy.

Dendritic cells (DC) are the most potent immunostimulatory cells, with the capacity to induce primary T-cell responses. Functional autologous DC can be generated from fetal calf serum-free peripheral blood mononuclear cells in the presence of interleukin-4 and granulocyte-macrophage colony-stimulating factor and are stimulated with a defined cytokine cocktail for terminal maturation. We were able to establish a nonviral transfection protocol for these DC by electroporation. Using enhanced green fluorescent protein as a reporter gene, we achieved transfection efficiencies of up to 10%. FACScan analyses revealed a stable phenotype, and the expression of major histocompatibility complex class II and CD83 was not affected by the transfection conditions used. Like their untransfected counterparts, DC that were functionally transfected with green fluorescent protein were potent inducers of allogeneic T cells. To assess whether cDNAs transfected into DC are functionally expressed, human tyrosinase cDNA was transfected into DC. Tyrosinase-transfected DC, but not controls, resulted in antigen-specific tumor necrosis factor-alpha release of the tyrosinase-specific cytolytic T-cell clone IVSB. Taken together, the data show that genuine (CD83+) mature DC can be transfected using a nonviral method, and that the DC retain their functionality. These DC are ideal candidates for immunotherapy (e.g., cancer therapy).

Antigens, CD↗