A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B.

IMPORTANCE: Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/ßc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/ßc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/ßc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. SIGNIFICANCE: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.

[Mechanism of artesunate on bone destruction in experimental rheumatoid arthritis based on transcriptomics and network pharmacology].

The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.

Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis.

The pathogenic role of the interleukin 21 (IL-21) in different autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit different activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining different clinical effects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective effect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modification of the immunological profile of the animals treated with the AAV8.sIL21R. The beneficial effect of the treatment was also observed when inducing the expression of the therapeutic molecule once the first neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the different clinical stages and its key role in the EAE immunopathogenesis.

A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells.

OBJECTIVE: The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two ß-subunits (p40 and EBI3). However, a ß-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation. METHODS: The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA. RESULTS: Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1ß, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner. CONCLUSION: In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Biomimetic anti-inflammatory nano-capsule serves as a cytokine blocker and M2 polarization inducer for bone tissue repair.

Controlling of pro-inflammation induced by pro-inflammatory cytokines and anti-inflammatory response induced by M2 macrophages is important for osteogenesis in the process of bone tissue repair. Thus, we fabricated biomimetic anti-inflammatory nano-capsule (BANC) that can block cytokines and promote M2 macrophage polarization, presenting a positive role for bone tissue repair. The BANC is a biomimic nanosystem, coated with lipopolysaccharide-treated macrophage cell membranes with cytokine receptors enveloping gold nanocage (AuNC) as "cytokine blocker", and loaded with resolvin D1 inside into AuNC as "M2 polarization inducer" whose controlled-release could be triggered under near-infrared laser irradiation in sequence, and these chronological events were consistent with the healing process of bone tissue repair. Moreover, in vivo application of femoral bone defects revealed that the BANC composite boron-containing mesoporous bioactive glass scaffolds improved the final effects of bone tissue repair through preventing inflammatory response, promoting M2 polarization in sequence in accord with the in vitro investigation. Hence, cytokine neutralization and M2 macrophage polarization enables the BANC to enhance the bone tissue repair as a biomimetic anti-inflammation effector. Therefore, this study provides potential therapeutic strategies for trauma-mediated or inflammation-related bone defects based on a biomimetic nanomaterial with weakened pro-inflammatory and enhanced anti-inflammatory effects. STATEMENT OF SIGNIFICANCE: Cell membrane-mimic nanomaterials have been popular for blocking natural cell responses for some infection diseases, yet their role in biological process of bone repair is unknown. Here, we fabricated Biomimetic Anti-inflammatory Nano-Capsule (BANC), coated with cell membrane with cytokines receptors on the surface which could neutralize the pro-inflammatory cytokine receptor to block activated pro-inflammation, loaded with Resolvin D1 inside which could be controllably released by NIR irradiation to promote M2 macrophage polarization for the following bone formation during the process of bone repair. Administration of BANC as cytokines blocker and M2 polarization inducer to enhance the bone regeneration, thus presenting a promising potential for the treatment of bone repair and regeneration.

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.

Esquistossomose mansônica humana: avaliação do receptor antagonista de IL-13 (IL-13Ra2) e da resposta imune celular / Human schistosomiasis: evaluation of receptor antagonist IL-13 (IL-13ra2) and cellular immune responses

Estudos indicam que citocinas Th1 (IL-2, TNF-alfa e IFN-gama) reduzem a fibrose na esquistossomose mansônica, enquanto que as Th2 (IL-4, IL-5, IL-6, IL-10 e IL-13) tem papel crítico na patogênese da doença. O desenvolvimento da resposta Th2 é dependente de IL-4, mas estudos revelaram a IL-13 como a mediadora da fibrose. Os mecanismos de controle da IL-13 estão ligados aos receptores desta citocina. O receptor IL-13Ra2, conhecida como receptor antagonista se liga com alta afinidade a IL-13, e estudos identificaram a sua participação na diminuição da fibrose e tamanho do granuloma. O principal objetivo desse projeto é avaliar o papel do IL-13Ra2 e da resposta imune celular nos diferentes graus de fibrose hepática e nas formas clínicas da esquistossomose mansônica humana. Os pacientes com diversas formas clínicas foram selecionados no Ambulatório de Gastroenterologia do HC- UFPE e avaliados através da ultrassonografia. As citocinas Th1 e Th2 foram dosadas através de citometria de fluxo e ELISA (IL-13 e IFN-gama), para a análise estatística foram utilizados testes de Mann-Whitney e Kruskal-Wallis e o teste de correlação de Spearman considerando um p 0,05 como significativo. Foi encontrado uma correlação negativa (p 0,05) entre o IL-13Ra2 e a IL-13, sugerindo um aumento da citocina no início da fibrose. Foi encontrada correlação inicialmente negativa nos pacientes sem fibrose e posteriormente positiva, nos pacientes com fibrose grave, entre IFN-gama e IL-13, salientando um novo mecanismo de regulação no processo de fibrose periportal na doença. Houve correlação positiva entre as citocinas do perfil Th1 e entre as citocinas do perfil Th2, sugerindo falta de supressão imunológica e presença de ambas às respostas, regulando a doença, com diferentes graus de fibrose periportal. Os resultados contribuirão para um melhor entendimento sobre os mecanismos imunes que controlam o processo de fibrogênese hepática em humanos e poderão ainda permitir um melhor entendimento da relação entre resposta imune celular e esquistossomose mansônica.

Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury.

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor-like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL-6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4(+) T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine interferon-γ. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung.

A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells.

Recent studies show that thymic stromal lymphopoietin (TSLP) plays a critical role in the upstream phase of the allergic cascade to induce T helper type 2 cell (Th2)-dominant allergic diseases. However, the effect of blocking TSLP signalling with the soluble TSLP receptor (TSLPR), TSLPR-immunoglobulin (Ig), on asthma development needs further investigation. Here, we examined the effects of TSLPR-Ig on asthmatic airway inflammation and dendritic cell (DC) function. TSLPR-Ig (comprising the extracellular domain of murine TSLPR and an IgG2a Fc tail) purified from transfected COS-7 cells reduced the expression of CD40, CD80 and CD86 on TSLP-activated DCs in vitro. We also investigated the mechanisms underlying TSLPR-Ig-mediated amelioration of allergic airway inflammation in a murine asthma model. When TSLP signalling was blocked by intratracheal administration of TSLPR-Ig prior to sensitization, allergen-specific serum IgE levels, airway tissue inflammation, inflammatory cell infiltration and Th2 cytokine levels in the bronchiolar lavage fluid (BALF) were reduced significantly. This was because of the TSLP-Ig-mediated down-regulation of co-stimulatory molecule expression on pulmonary DCs. We also transferred bone marrow-derived mature DCs (mDCs) into the airways of asthmatic mice. Intratracheal administration of TSLPR-Ig prior to the transfer of mDCs reduced eosinophilic airway inflammation and Th2 differentiation significantly. Collectively, these data suggest that local use of TSLPR-Ig prevents airway inflammation, at least in part, by regulating DC function, and that blocking TSLP signalling using TSLPR-Ig may be a novel strategy for the treatment of asthma bronchiale.

Immunomodulators in asthma therapy.

New developments in the field of allergy and immunology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxynucleotides, orally and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor-gamma, and nuclear factor-kappaB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to benefit from it are less clear. This review summarizes data from human clinical trials with immunomodulators to discuss the rationale for their use, their efficacy, and adverse events associated with them.

Anti-cytokine therapeutics: history and update.

Anti-cytokine therapy has promoted a revolution in the treatment of several inflammatory disorders during the past 10 years. Despite their medical and commercial success, they exhibit several drawbacks: difficulties of production, excessive costs, and a few side-effects. A promising alternative to the passive infusion of monoclonal antibodies or soluble cytokine receptors is the use of the active anti-cytokine immune therapy (ACIT). Surprisingly, clinical studies suggested the interest of this approach during the late 1980's, even before the advent of anti-cytokine passive immunotherapy. In this review, we first explain the involvement of several cytokines in many common diseases involving cytokine overproduction, and identify key targets for anti-cytokine treatments. We then present an update on current advances in preclinical and clinical development of passive anti-cytokine therapeutic approaches. We further discuss progresses in the promising field of active anti-cytokine immunotherapy. Cytokine receptors biologics and small molecules developed using structure/function information, which also constitute important options for treating the cytokine-mediated diseases, are not discussed in this review.

Papel dos Receptores do tipo Toll na malária

Desde sua descoberta, os receptores do tipo Toll (TLRs) têm sido envolvidos em quase todas as doenças que afetam a saúde humana. Seu papel na proteção contra vários patógenos, incluindo protozoários está bem estabelecido. Entretanto, pouco se sabe sobre o papel dos TLRs na malária. No presente estudo, investigamos o papel dos TLRs. durante a malária murina e humana. Nossos resultados mostraram que camundongos com deficiência para MyD88, um adaptador essencial para a sinalização dos TLRs, produzem níveis de citocinas pró-inflamatórias significativamente menores e apresentam sintomas mais amenos durante a infecção por Plasmodium chabaudi. Entretanto, estes animais retêm a capacidade de controlar a parasitemia sugerindo que os TLRs possuam um papel na patogênese e não na proteção contra a malária. Posteriormente, mostramos que ambas, a infecção natural humana por P. falciparum e a experimental murina por P. chabaudi, aumentam a expressão e a responsividade dos TLRs nas células do sistema imune inato. O estado hiper-responsivo das células durante a malária é derivado da ativação de TLR9 e a produção de IFN por células T, levando a uma alta susceptibilidade ao choque séptico durante a malária aguda. Finalmente, em colaboração com a EISAI Research Institute, desenvolvemos um antagonista de TLR9 e testamos seu efeito na Malária Cerebral (CM), uma das manifestações clínicas mais graves da malária. O tratamento oral com este composto inibiu os sintomas, tais como. extravasamento vascular cerebral, protegendo camundongos da morte por CM. Em conjunto, nossos resultados mostram um importante papel dos TLRs, especialmente TLR9, na patogênese da malária e que a intervenção na função destes receptores é uma potencial quimioterapia anti-inflamatória contra essa doença

Papel dos receptores do tipo toll na malária / Role of toll-like receptors in malaria

Desde sua descoberta, os receptores do tipo Toll (TLRs) têm sido envolvidos em quase todas as doenças que afetam a saúde humana. Seu papel na proteção contra vários patógenos, incluindo protozoários está bem estabelecido. Entretanto, pouco se sabe sobre o papel dos TLRs na malária. No presente estudo, investigamos o papel dos TLRs. durante a malária murina e humana. Nossos resultados mostraram que camundongos com deficiência para MyD88, um adaptador essencial para a sinalização dos TLRs, produzem níveis de citocinas pró-inflamatórias significativamente menores e apresentam sintomas mais amenos durante a infecção por Plasmodium chabaudi. Entretanto, estes animais retêm a capacidade de controlar a parasitemia sugerindo que os TLRs possuam um papel na patogênese e não na proteção contra a malária. Posteriormente, mostramos que ambas, a infecção natural humana por P. falciparum e a experimental murina por P. chabaudi, aumentam a expressão e a responsividade dos TLRs nas células do sistema imune inato. O estado hiper-responsivo das células durante a malária é derivado da ativação de TLR9 e a produção de IFN por células T, levando a uma alta susceptibilidade ao choque séptico durante a malária aguda. Finalmente, em colaboração com a EISAI Research Institute, desenvolvemos um antagonista de TLR9 e testamos seu efeito na Malária Cerebral (CM), uma das manifestações clínicas mais graves da malária. O tratamento oral com este composto inibiu os sintomas, tais como. extravasamento vascular cerebral, protegendo camundongos da morte por CM. Em conjunto, nossos resultados mostram um importante papel dos TLRs, especialmente TLR9, na patogênese da malária e que a intervenção na função destes receptores é uma potencial quimioterapia anti-inflamatória contra essa doença

Many cytokines are very useful therapeutic targets in disease.

Cytokines are a large family of more than 100 small proteins that function as short-range mediators involved in essentially all biological processes. They have been found to be important rate-limiting signals, and it is now known that blocking some cytokines, e.g., TNF-alpha, and cytokine receptors, such as human EGFR 1 (HER1) or HER2, yields effective therapeutics that address unmet needs. This Review Series surveys three chronic inflammatory disease areas and two forms of cancer and discusses the important role of cytokines and their receptors in these disease processes. Their role as potential therapeutic targets is also highlighted.

Chemokine receptors : therapeutic potential in asthma.

Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.

[Treatment of allergic rhinitis: update 2005]. / Therapie der allergischen Rhinitis. Mannschaftsaufstellung für die Allergiesaison 2005.

Potential approaches to the treatment of allergic rhinitis are the avoidance of allergens and medication with chromone compounds, antihistaminics and glucocorticosteroids. The sole causally effective treatment is specific immunotherapy. Leukotriene receptor antagonists, anti-IgE antibodies and monoclonal CD-4-molecules, as also soluble cytokine receptors are potential therapeutic options, the value of which currently remains unknown.

Receptor-based design of cytokine therapeutics.

Cytokines hold huge potential for the treatment of disease due to their often fundamental roles in development and homeostasis. However, it is this same primary biological function that can both cause disease through dysregulation as well as prevent their therapeutic use due to systemic consequences arising from this inherent pleiotropy. Molecularly, this can be explained through an understanding of the receptor system specific to each cytokine and the cells on which they are expressed. This knowledge has been exploited to yield muteins (mutated proteins) that exhibit selective, and sometimes novel, biological properties dependent upon receptor subunit usage. In some cases, these muteins have been evaluated in clinical trials and have been approved for clinical use; in most instances, however, these muteins are not suitable for therapeutic application due to intrinsic characteristics of the muteins themselves or the cellular and receptor system to which they are directed. Ultimately, molecular insight to the biological processes governing disease pathology underlies the successful application of mutein-based therapy. The clinical success enjoyed by a subset of these proteins signals the advent of a new mode of therapeutic protein development.