646 research outputs found
Regulatory T Cells
Immunologic self-tolerance is critically dependent on the induction but also on the downregulation of immune responses. Though ignored and neglected for many years, suppressor T cells, now renamed regulatory T cells (Tregs), play an important role in the negative regulation of immune responses. Several subsets of Tregs have been described. Naturally occurring CD4+CD25+ Tregs are important in the prevention of autoimmune diseases. Type 1 Tregs, another subtype of Treg that is inducible, exert their suppressive activity primarily via the release of IL-10. Detailed knowledge about the phenotype and mode of action of these cells will significantly increase our understanding of the pathogenesis of autoimmune diseases and will also help to identify new therapeutic strategies
Molekulares Targeting des BCR/ABL-Translokationsprodukts als Therapieansatz fĂŒr Philadelphia-Chromosom-positive LeukĂ€mien
Das Philadelphia-Chromosom (Ph) ist das zytogenetische Korrelat der t(9;22). 95% der chronisch myeloischen LeukĂ€mien (CML) und 20-25% der akuten lymphatischen LeukĂ€mien (ALL) des Erwachsenen sind Ph-positiv (Ph+). Die t(9;22) fĂŒhrt zur Expression des chimĂ€ren BCR/ABL Fusionsproteins, das fĂŒr die Pathogenese der Ph+ LeukĂ€mien verantwortlich ist. Das ABL-Protein ist eine nicht-Rezeptor Tyrosinkinase. Im BCR/ABL-Fusionsprotein wird die Kinase-AktivitĂ€t von ABL, die im Normalfall streng reguliert ist, durch die Fusion mit BCR konstitutiv aktiviert. Die N-terminale BCR-"coiled-coil" DomĂ€ne vermittelt die Oligomerisierung des Fusionsproteins und dadurch zur Aktivierung der ABL-Kinase. Dies fĂŒhrt zur malignen Transformation hĂ€mopoetischer Zellen. Der ABL-Kinaseinhibitor STI571 ist ein tumorzellspezifisches Therapeutikum fĂŒr Ph+ LeukĂ€mien, das bei der Mehrzahl der Patienten zur hĂ€matologischen Vollremission fĂŒhrt. Insbesondere bei Patienten mit CML-Blastenkrise und Ph+ ALL kommt es durch klonale Selektion STI571-resistenter Zellen zu einem frĂŒhen Therapie-refraktĂ€ren Rezidiv der Krankheit. Ziel dieser Arbeit war es, die Grundlagen fĂŒr neue, tumorzellspezifische Therapiestrategien fĂŒr die Behandlung BCR/ABL-positiver LeukĂ€mien zu legen. Im ersten Teil der Arbeit sollte geklĂ€rt werden, ob sich die "coiled-coil" DomĂ€ne als Zielstruktur fĂŒr einen molekularen Therapieansatz eignet: es wurde untersucht, ob eine Hemmung der Oligomerisierung das Transformationspotential von BCR/ABL negativ beeinfluĂt. Der Zusammenhang zwischen Oligomerisierung und Transformationspotential von BCR/ABL wurde mit Hilfe verschiedener Fusionskonstrukte untersucht, bei denen die OligomerisierungsdomĂ€nen verschiedener Proteinen, (BCR, PML, PLZF und TEL) mit dem ABL-Teil von BCR/ABL fusioniert wurden (X-ABL). Es konnte gezeigt werden, daĂ ein direkter Zusammenhang zwischen der Oligomerisierung, Transformationspotential und STI571-SensitivitĂ€t besteht: verstĂ€rkte Oligomerisierung der X-ABL Konstrukte fĂŒhrte zu einem ein höheren Transformationspotential und einer geringeren STI571-SensitivitĂ€t und umgekehrt. AuĂerdem wurde gezeigt, daĂ die Inhibierung der Oligomerisierung mit Hilfe eines rekombinanten Peptids das Transformationspotential von BCR/ABL erniedrigt und gleichzeitig die SensibilitĂ€t gegenĂŒber STI571 stark erhöht. Diese Ergebnisse zeigen, daĂ die OligomerisierungsdomĂ€ne von BCR/ABL einen therapeutischer Angriffspunkt fĂŒr die Behandlung Ph+ LeukĂ€mien darstellt. Im zweiten Teil der Arbeit wurde der Tumorzell-spezifische Mechanismus der As2O3-induzierten Apoptose bei Ph+ Zellen untersucht. KĂŒrzlich wurde gezeigt, daĂ aktiviertes RAS die Expression von endogenem PML hochreguliert. RAS wird durch BCR/ABL konstitutiv aktiviert. Bei der Akuten PromyelozytenleukĂ€mie (APL) ist PML im Rahmen der t(15;17) durch die Fusion mit RARa modifiziert. Die Behandlung von Zellen mit As2O3 fĂŒhrt zur Modifikation von PML durch den "small ubiquitin like modifier" (SUMO-1). Im Rahmen dieser Arbeit konnte gezeigt werden, daĂ sich die Gemeinsamkeiten zwischen Ph+ CML und ALL-Blasten und den t(15;17) positiven APL-Blasten in Hinsicht auf die SensibilitĂ€t fĂŒr die As2O3-induzierte Apoptose auf die direkte oder indirekte Modifikation von PML durch die jeweiligen Translokationsprodukte zurĂŒckfĂŒhren lassen. In dieser Arbeit wurde mittels Ăberexpression von PML und konstitutiv aktiviertem RAS (RASV12) gezeigt, daĂ BCR/ABL durch Aktivierung des RASSignalweges die PML-Expression modifiziert und die As2O3-induzierte Apoptose Ph+ Zellen somit durch PML vermittelt wird. An einem Mausmodell der Ph- LeukĂ€mie wurde die Wirkung von As2O3 auf die normale HĂ€mopoese sowie auf die BCR/ABL-positive LeukĂ€mie ĂŒberprĂŒft. Es konnte gezeigt werden, daĂ As2O3 die normale HĂ€mopoese nicht stört und bei 25% der behandelten Tiere zu einer Verbesserung des Blutbildes und einem lĂ€ngerem Ăberleben fĂŒhrt. Sowohl das therapeutische Angreifen an der OligomerisierungsoberflĂ€che von BCR/ABL als auch das AusnĂŒtzen der Modifikation von PML durch BCR/ABL eröffnen neue Möglichkeiten zur Behandlung von Ph+ LeukĂ€mien
Improvement of cutaneous inflammation and panniculitis in patients with dermatomyositis by the Janus kinase inhibitor baricitinib
Dear Editor, Dermatomyositis (DM) is a rare autoimmune disease with cutaneous and systemic involvement significantly impairing quality of life. Current treatment options are unspecific and often induce only partial remission, especially in DMâassociated panniculitis. The pathogenesis of the disease is fairly unknown; however, induction of type I interferon (IFN) and its IFNâstimulated genes (ISGs) was discovered in patientsâ blood, muscle and skin.1 Inhibiting the activation of Janus kinase (JAK)âtransmitting signals of the type I IFN receptor is a valuable therapeutic option, and the efficacy of the JAK1 and JAK2 inhibitor baricitinib was reported in eight patients with juvenile DM and in two patients with adult DM.2â6
The prominent type I IFN signature in DM prompted us to treat three patients with classic adult DM with the JAK inhibitor baricitinib.1 Patient 1 had experienced a recurrent disease course for 25 years. She had previously received immunosuppressive therapy and intravenous immunoglobulin (IVIG). Partial remission was achieved with lowâdose prednisolone (5 mg per day), methotrexate, hydroxychloroquine and adalimumab. Nevertheless, she presented with a new disease flare with violaceous erythema prone to the face, dĂ©colletĂ©, neck and periungual area, but normal muscle enzymes (Figure 1a). The therapy with methotrexate and adalimumab was terminated due to an increase in liver enzymes. Thereafter, tofacitinib was started but was not well tolerated because of lactose intolerance in the patient. Therefore, the therapy was changed to baricitinib 4 mg daily. The neck, facial and periungual erythema completely regressed within 5 months of treatment (Figure 1a)
Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma
Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively
The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critically Involved in the Development of Cytotoxic CD8+ T Cells in Mice and Humans
BACKGROUND: The neuropeptide alpha-melanocyte-stimulating hormone is well known as a mediator of skin pigmentation. More recently, it has been shown that alpha-melanocyte-stimulating hormone also plays pivotal roles in energy homeostasis, sexual function, and inflammation or immunomodulation. Alpha-melanocyte-stimulating hormone exerts its antiinflammatory and immunomodulatory effects by binding to the melanocortin-1 receptor, and since T cells are important effectors during immune responses, we investigated the effects of alpha-melanocyte-stimulating hormone on T cell function. METHODOLOGY/PRINCIPAL FINDINGS: T cells were treated with alpha-melanocyte-stimulating hormone, and subsequently, their phenotype and function was analyzed in a contact allergy as well as a melanoma model. Furthermore, the relevance of alpha-melanocyte-stimulating hormone-mediated signaling for the induction of cytotoxicity was assessed in CD8(+) T cells from melanoma patients with functional and nonfunctional melanocortin-1 receptors. Here we demonstrate that the melanocortin-1 receptor is expressed by murine as well as human CD8(+) T cells, and we furthermore show that alpha-melanocyte-stimulating hormone/melanocortin-1 receptor-mediated signaling is critical for the induction of cytotoxicity in human and murine CD8(+) T cells. Upon adoptive transfer, alpha-melanocyte-stimulating hormone-treated murine CD8(+) T cells significantly reduced contact allergy responses in recipient mice. Additionally, the presented data indicate that alpha-melanocyte-stimulating hormone via signaling through a functional melanocortin-1 receptor augmented antitumoral immunity by up-regulating the expression of cytotoxic genes and enhancing the cytolytic activity in tumor-specific CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Together, these results point to an important role of alpha-melanocyte-stimulating hormone in MHC class I-restricted cytotoxicity. Therefore, treatment of contact allergies or skin cancer with alpha-melanocyte-stimulating hormone or other more stable agonists of melanocortin-1 receptor might ameliorate disease or improve antitumoral immune responses
Identifying gaps and providing recommendations to address shortcomings in the investigation of acne sequelae by the Personalising Acne: Consensus of Experts panel
Background: The physical sequelae of acne include erythema, hyperpigmentation, and scarring, which are highly burdensome for patients. Early, effective treatment can potentially limit and prevent sequelae development, but there is a need for guidance for and evidence of prevention-oriented management to improve patient outcomes.
Objective: To identify unmet needs of acne sequelae and generate expert recommendations to address gaps in clinical guidance.
Methods: The Personalizing Acne: Consensus of Experts panel of 13 dermatologists used a modified Delphi approach to achieve a consensus on the clinical aspects of acne sequelae. A consensus was defined as â„75% of the dermatologists voting agree or strongly agree. All voting was electronic and blinded.
Results: The panel identified gaps in current guidance and made recommendations related to acne sequelae. These included identification and classification of sequelae, pertinent points to consider for patient consultations, and management aimed at reducing the development of sequelae.
Limitations: The recommendations are based on expert opinion and made in the absence of high-quality evidence.
Conclusions: The identified gaps should help inform future research and guideline development for acne sequelae. The consensus-based recommendations should also support the process of consultations throughout the patient journey, helping to reduce the development and burden of acne sequelae through improved risk factor recognition, early discussion, and appropriate management
The Personalised Acne Care Pathway-Recommendations to guide longitudinal management from the Personalising Acne: Consensus of Experts
Background: Acne is a chronic disease with a varying presentation that requires long-term management. Despite this, the clinical guidelines for acne offer limited guidance to facilitate personalized or longitudinal management of patients.
Objectives: To generate recommendations to support comprehensive, personalized, long-term patient management that address all presentations of acne and its current and potential future burden.
Methods: The Personalising Acne: Consensus of Experts panel consisted of 13 dermatologists who used a modified Delphi approach to reach consensus on statements related to longitudinal acne management. The consensus was defined as â„75% voting agree or strongly agree. All voting was electronic and blinded.
Results: Key management domains, consisting of distinct considerations, points to discuss with patients, and pivot points were identified and incorporated into the Personalised Acne Care Pathway. Long-term treatment goals and expectations and risk of (or fears about) sequelae are highlighted as particularly important to discuss frequently with patients.
Limitations: Recommendations are based on expert opinion, which could potentially differ from patients\u27 perspectives. Regional variations in health care systems may not have been captured.
Conclusions: The Personalised Acne Care Pathway provides practical recommendations to facilitate the longitudinal management of acne, which can be used by health care professionals to optimize and personalize care throughout the patient journey
Spontaneous tumor rejection by cbl-bâdeficient CD8+ T cells
The concept of tumor surveillance implies that specific and nonspecific components of the immune system eliminate tumors in the early phase of malignancy. Understanding the biochemical mechanisms of tumor immunosurveillance is of paramount significance because it might allow one to specifically modulate spontaneous antitumor activity. We report that inactivation of the E3 ligase Casitas B cell lymphoma-b (Cbl-b) confers spontaneous in vivo rejection of tumor cells that express human papilloma virus antigens. Moreover, cbl-bâ/â mice develop significantly fewer ultraviolet B (UVB)âinduced skin malignancies and reject UVB-induced skin tumors. CD8+ T cells were identified as key players in the spontaneous tumor rejection response. Loss of Cbl-b not only enhances antitumor reactivity of CD8+ T cells but also occurs in the absence of CD4+ T cells. Mechanistically, cbl-bâ/â CD8+ T cells are resistant to T regulatory cellâmediated suppression and exhibit enhanced activation and rapid tumor infiltration. Importantly, therapeutic transfer of naive cbl-bâ/â CD8+ T cells is sufficient to mediate rejection of established tumors. Even up to 1 yr after the first encounter with the tumor cells, cbl-bâ/â mice carry an âanticancer memory.â These data identify Cbl-b as a key signaling molecule that controls spontaneous antitumor activity of cytotoxic T cells in different cancer models. Inhibition of Cbl-b is a novel approach to stimulate long-lasting immunity against cancer
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