Etanercept therapy of psoriatic arthritis in a patient with liver cirrhosis.
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Arthritis, Psoriatic↗
Biomedical subjects
Stephan Grabbe
Publications and source records attributed to Stephan Grabbe.
A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo.
For activation T cells engage antigen-presenting cells (APCs) in lymphatic tissues. The contact duration and kinetics (static versus dynamic) vary considerably in different model systems; however, it is unclear whether T cells, APCs, or the environment are responsible for the observed discrepancies. Using 3-D collagen matrices as structural scaffold, we directly compared the kinetics of T-cell engagement and activation by functionally major APC types, ie, dendritic cells (DCs) and resting or activated B cells. Resting B cells engaged T cells in long-lived (several hours), adhesive, and leukocyte function-associated antigen-1 (LFA-1)-dependent conjugates in 3-D collagen as well as in intact lymph nodes in vivo. DCs and preactivated B cells, however, supported predominantly dynamic, short-lived (minutes), and sequential contacts to T cells that were dependent on high cytoskeletal activity of the APCs but could not be inhibited by anti-LFA-1 treatment. Naive T cells were most strongly activated by DCs and activated B cells, whereas resting B cells were 100-fold less efficient to induce T-cell proliferation. Thus, in the same 3-D environment, naive T cells respond with a spectrum of different interaction modes dependent on the type and activation state of the APCs. Thereby, more dynamic interaction kinetics is positively correlated with higher T-cell priming efficiency.
Animals↗
Radiotherapy of benign diseases-scleredema adultorum Buschke.
BACKGROUND: Scleredema adultorum Buschke is a rare disorder characterized by thickening of the dermis of the neck, head and upper trunk. Its etiology is unknown, but there may be a preceding history of infection and there is a known association with diabetes mellitus. Women are more frequently affected. Usually, the disease is self-limiting but some patients show progressive disease. In these cases therapeutic options are poor, with only case reports and small series supporting their use. CASE REPORT: A 58-year-old patient with a scleredema of the neck and upper trunk is described, who was treated twice within 6 months by electron-beam radiation therapy. After the second course his symptoms improved significantly. A review of the literature of radiation treatment of this disease is given. CONCLUSION: . Regardless of the possible mechanisms in pathogenesis and treatment of scleredema adultorum Buschke, the application of ionizing radiation is an important, effective and well-tolerated therapy option in the treatment of severe cases and may candidate as the first-line treatment of this disease.
Humans↗
DCs and CD40-activated B cells: current and future avenues to cellular cancer immunotherapy.
Despite the still poorly understood complexity of tumor-host immune interactions, the use of cellular vaccines (particularly dendritic cells) has made it possible to reliably generate tumor antigen-specific T cells, both in animal models and in humans. These encouraging pre-clinical results have led to a translation of these immunotherapeutic strategies into clinical trials. With numerous trials still underway, their general outcome has so far been disappointing, and the discrepancy between pre-clinical data and clinical response rates is striking. Thus, either the pre-clinical models have not been representative of the human situation or the translation into human clinical trials is still sub-optimal. Here we suggest new avenues of clinical research to further improve cellular cancer immunotherapy.
Animals↗
[G-DRG Version 2004: changes in view of dermatology].
In the year 2004 the obligatory introduction of the new hospital funding system based on a Diagnosis Related Groups (DRG) system will become reality for all German hospitals. After all fundamental items of the new G-DRG version were made generally known, the possible consequences had to be considered. The first mandatory German case-based lump sum catalogue differs importantly from the previous payment models and requires intensive study. Economic considerations will increasingly play a role in the daily routine of hospitals and influence treatment patterns. Therefore, comprehensive knowledge of basic principles of G-DRG is essential. In the following aspects of the reimbursement system with special relevance to dermatology are reviewed in detail. Additionally, the revised classification system versions OPS-301 SGB V and ICD-10-GM 2004 and the German coding standards version 2004 must be appropriately applied for dermatologic purposes.
Dermatology↗
[Thromboangiitis obliterans: an overview].
Thromboangiitis obliterans is a vascular disease characterized by a segmental, non-atherosclerotic inflammation of the small and medium-sized arteries and veins. The vascular changes are mainly found on the distal extremities. Involvement of visceral organs is rare. Affected patients are mostly young male smokers, who develop ulcers and gangrene of the toes and fingers as a result of the vascular ischaemia. Diagnosis is made using characteristic clinical criteria as well as pathological findings in arteriography and histopathology. Although the exact underlying causes of Buerger's disease are still unknown, the disease is strongly associated with tobacco smoking. Although most investigators speculate about an autoimmune mechanism, no causative antigens have yet been discovered. The only definite form of therapy is the discontinuation of tobacco use. On the basis of smoking cessation, further therapies (e.g. administration of prostacyclin analoga) are possible. The mortality rate for patients with Buerger's disease is not higher than that for the rest of the adult population, but patients often require minor and major limb amputation due to ulcerations.
Female↗
[Syphilis with HIV coinfection].
In recent years a rising incidence of syphilis has been observed, especially in the population of homosexual men. Because of altered sexual behavior in terms of increased promiscuity paralleled by decreased use of condoms and the fact that a syphilis infection increases the susceptibility to HIV coinfection, the incidence of HIV is also rising once again in this population. In patients with HIV coinfection, the course of syphilis is often atypical or dramatic. Stage-specific features suggesting coinfection include prolonged primary ulcers persisting well into the secondary stage, numerous atypical cutaneous findings in the second stage and a rapid progression from stage to stage. The diagnosis of syphilis may be more difficult because of false positive or false negative serological findings in patients with HIV coinfection. Whether or not the CNS is more often involved is this patient group has not been established by prospective studies and remains controversial. However, WHO and CDC recommendations include evaluation of the CSF in HIV-infected patients with either late syphilis or when the time course is unknown period. There is worldwide agreement on the therapy of syphilis in patients with HIV coinfection. Patients with early syphilis should be treated with 2.4 benzathine penicillin i.m. once or twice; patients with late syphilis, twice or three times. Patients presenting with clinical or serological signs of neurosyphilis require 18-24 million IU penicillin i.v. daily for at least 2 weeks.
Female↗
Senescent BALB/c mice are able to develop resistance to Leishmania major infection.
Aging has been associated with a decline in immunocompetence and resistance to infections, partially due to dysregulated NO production by macrophages and deficits in mounting Th2 cell responses. We wondered if these alterations would reverse the immune response in experimental leishmaniasis. Bone-marrow-derived macrophages from 2- and 18-month-old (senescent) C57BL/6 or BALB/c mice showed no marked difference in leishmanicidal functions. In vivo infections of resistant C57BL/6 mice with Leishmania major revealed no difference between senescent and young mice. However, among susceptible BALB/c mice, senescent animals showed less foot-pad swelling than young mice, and 40 to 60% of them even showed healing of ulcers, reduced parasite dissemination, and a Th1 cell response. These changes were associated with a spontaneous release of interleukin-12 (IL-12) by macrophages from aged but not from young mice. Since exogenous microbial stimulation can influence immune responses during aging, we also infected senescent mice who were raised under specific-pathogen-free (SPF) conditions. They showed neither resistance nor a Th1 response, but their macrophages still spontaneously released IL-12. A microbiological analysis showed that conventionally kept mice, but not SPF mice, had experienced infection with murine hepatitis virus (MHV), an infection associated with a Th1-like response. We conclude that for the reversal of the immune response, senescence is the premier requirement but needs to be completed by another mandatory event such as microbial stimulation. One of the age-related, but not environment-related, factors is the spontaneous release of IL-12 by macrophages, while confrontation with MHV presents an environment-related difference, with both having the potential to support a Th1 response.
Aging↗
CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis.
In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (beta(2) integrin) to 2-16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4(+) and CD8(+) T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4(+) T cells, and not the removal of CD8(+) T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4(+) T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4(+) T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2-16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4(+) T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.
Animals↗
Significant risk of a second melanoma in patients with a history of melanoma but no further predisposing factors.
It is a well-accepted fact that melanoma patients are prone to develop further melanomas. In a cohort of 535 melanoma patients, we determined the incidence of second melanomas, as well as risk factors known to be associated with melanoma development. A retrospective analysis of patients regularly consulting our melanoma care unit revealed second or even further melanomas in 5.6% (n = 30). When compared to the overall population, melanoma patients have at least a 30-fold increased risk for the development of a second melanoma. Twenty of these 30 patients revealed none of the known predisposing conditions for multiple melanomas.
Female↗
Monocyte and macrophage functions in M-CSF-deficient op/op mice during experimental leishmaniasis.
Mice with a naturally occurring Csfm(op)/Csfm(op) (op/op) gene mutation lack functional macrophage-colony stimulating factor (M-CSF) and are deficient of M-CSF-derived macrophages. They are severely monocytopenic, and their remaining M-CSF-independent macrophages were shown to differ in differentiation and distinct functions when compared with phenotypically normal mice of the same background. It is not known if osteopetrosis mice (op/op mice) are able to mount a specific immune response against intracellular pathogens, as this would require complex effector functions by macrophages. We therefore investigated the ability of op/op mice and their M-CSF-independent macrophages to combat infection with Leishmania major. op/op mice retained the ability to resist an infection with L. major by mounting a T helper cell type 1 cell response, eliminating parasites and resolving the lesions. Macrophages from op/op mice were able to sufficiently perform effector functions in vitro, such as phagocytosis, production of leishmanicidal nitric oxide (NO), killing of parasites, and release of interleukin (IL)-12. There were quantitative differences, as M-CSF-derived macrophages from hematopoietic organs of control mice showed significantly higher rates of phagocytosis and higher NO release after stimulation with lipopolysaccharides than corresponding macrophages from op/op mice. In contrast, when peritoneally elicited macrophages were used, those from op/op mice revealed a stronger response than those from control mice with regard to release of NO or IL-12. These differences suggest that M-CSF-independent maturation of op/op monocytes subsequent to their release from hematopoietic tissue exerts influence on their effector functions. However, M-CSF or M-CSF-derived macrophages are not necessary for an effective immune response against L. major.
Animals↗
[Pathomechanisms of the elicitation phase of allergic contact dermatitis].
Allergic contact dermatitis (ACD) is a T-cell mediated, antigen-specific inflammatory response to repeated epicutaneous exposure to haptens. Two immunologically distinct sequential steps are required to produce the clinical picture of ACD. In the sensitization phase, naïve antigen-specific T cells are primed and differentiate into memory or effector T cells. In the elicitation phase, reapplication of the same hapten leads to local recruitment of hapten-specific T cells which are cytotoxic, release cytokines and recruit other inflammatory cells. These events lead to clinically visible tissue inflammation characterized by edema, erythema, scaling, and blistering. For the clinician, the effector phase is especially important, because sensitization is generally asymptomatic, whereas elicitation produces the clinical picture of ACD. Detailed knowledge about the mechanisms of the elicitation phase of ACD is needed in order to develop novel therapeutic approaches.
Cytokines↗
Immature mouse dendritic cells enter inflamed tissue, a process that requires E- and P-selectin, but not P-selectin glycoprotein ligand 1.
Inflammatory processes are associated with the rapid migration of dendritic cells (DCs) to regional lymph nodes and depletion of these potent antigen-presenting cells (APCs) from the inflamed tissue. This study examined whether sites of cutaneous inflammation can be repopulated with DCs from a pool of immature DCs circulating in the blood. In adoptive transfer experiments with ex vivo-generated radioactively labeled primary bone marrow-derived DCs injected into mice challenged by an allergic contact dermatitis reaction, immature DCs were actively recruited from the blood to sites of cutaneous inflammation, whereas mature DCs were not. Immature, but not mature, DCs were able to adhere specifically to immobilized recombinant E- and P-selectin under static as well as under flow conditions. P-selectin-dependent adhesion of immature DCs correlates with their higher level of expression of the carbohydrate epitope cutaneous lymphocyte-associated antigen (CLA) and is blocked by a novel inhibitory antibody against mouse P-selectin glycoprotein ligand 1 (PSGL-1). Surprisingly, however, emigration of immature DCs into inflamed skin is retained in the presence of this anti-PSGL-1 antibody and is also normal when immature DCs are generated from fucosyltransferase (Fuc-T) Fuc-TVII-deficient mice. By contrast, emigration of wild-type immature DCs is reduced by adhesion-blocking anti-E- and P-selectin antibodies, and immature DCs generated ex vivo from Fuc-TVII/Fuc-TIV double-deficient mice emigrate poorly. Thus, fucosylated ligands of the endothelial selectins, determined in part by Fuc-TIV, and independent of PSGL-1, are required for extravasation of DCs into sites of cutaneous inflammation.
Animals↗
Beta2 integrins are required for skin homing of primed T cells but not for priming naive T cells.
Beta2 integrins are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. To elucidate the role of beta2 integrins in T cell-mediated immune responses, allergic contact dermatitis (ACD), irritant dermatitis, and delayed-type hypersensitivity (DTH) were assessed in mice lacking the beta2 integrin subunit, CD18. ACD and DTH responses, but not edema formation, were severely suppressed in CD18(-/-) mice. Extravasation of CD18(-/-) T cells into eczematous skin lesions was greatly impaired, whereas migration of Langerhans cell precursors and dendritic cells was normal in CD18(-/-) mice. CD18(-/-)lymph nodes (LNs) contained an abnormal population of CD3(-)CD44(high) lymphocytes and showed evidence of widespread T cell activation. T cells from regional LNs of sensitized CD18(-/-) mice proliferated in response to hapten challenge, and subcutaneous injection of sensitized syngeneic LN cells directly into ears of hapten-challenged naive recipients restored the defective ACD in CD18(-/-) mice, suggesting that CD18 is not required for priming of naive T cells but is indispensable for T cell extravasation. Thus, a dysfunction of T cells, in addition to granulocytes, may contribute to the pathophysiology of leukocyte adhesion deficiency type I, which arises from mutations in the human CD18 gene.
Animals↗