Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

• MeSH
• cytokiny metabolismus   MeSH
• interleukin-2 * imunologie   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory imunologie   terapie   farmakoterapie   MeSH
• proteinové inženýrství metody   MeSH
• regulační T-lymfocyty imunologie   účinky léků   MeSH
• rekombinantní fúzní proteiny * farmakologie   imunologie   aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• cytokiny * farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• erythropoetin analogy a deriváty   farmakologie   klasifikace   terapeutické užití   MeSH
• faktor stimulující kolonie granulocytů farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• interferony farmakologie   imunologie   klasifikace   terapeutické užití   MeSH
• interleukin-1 farmakologie   imunologie   terapeutické užití   MeSH
• interleukin-2 farmakologie   imunologie   terapeutické užití   MeSH
• receptory cytokinové imunologie   klasifikace   MeSH
• thrombopoetin agonisté   farmakologie   klasifikace   terapeutické užití   MeSH
• TNF-alfa farmakologie   terapeutické užití   MeSH
• Publikační typ
• přehledy MeSH

Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.

• MeSH
• interleukin-2 * aplikace a dávkování   imunologie   MeSH
• lidé MeSH
• pilotní projekty MeSH
• regulační T-lymfocyty MeSH
• rejekce štěpu MeSH
• transplantace obličeje * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Hot water extract from biomass of heterotrophic mutant green alga Parachlorella kessleri HY1 (Chlorellaceae) was deproteinised, and three polysaccharidic fractions were obtained by preparative chromatography. The low-molecular fraction (1.5 × 104g mol-1) was defined mainly as branched O-2-β-xylo-(1→3)-β-galactofuranan where xylose is partially methylated at O-4. Two high-molecular fractions (3.05 × 105 and 9.84 × 104g mol-1) were complex polysaccharides containing α-l-rhamnan and xylogalactofuranan parts in different ratios. The polysaccharides were well soluble in hot water and, upon cooling, tended to self-segregate. Immunomodulatory activities of the obtained fractions were preliminary tested using ELISA, FACS and ImmunoSpot kits. The polysaccharides increased the TNF-α production in melanoma bearing mice with much higher intensity than in healthy mice. This was in agreement with the FACS results on T and B cells indicating their possibly secondary activation by innate immunity cells.

• MeSH
• B-lymfocyty účinky léků   imunologie   patologie   MeSH
• CD antigeny genetika   imunologie   MeSH
• Chlorophyta chemie   MeSH
• imunologické faktory chemie   izolace a purifikace   farmakologie   MeSH
• interferon gama genetika   imunologie   MeSH
• interleukin-2 genetika   imunologie   MeSH
• interleukin-4 genetika   imunologie   MeSH
• lipopolysacharidy antagonisté a inhibitory   farmakologie   MeSH
• melanom imunologie   patologie   MeSH
• metylace MeSH
• molekulová hmotnost MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory kůže imunologie   patologie   MeSH
• polysacharidy chemie   izolace a purifikace   farmakologie   MeSH
• primární buněčná kultura MeSH
• regulace genové exprese účinky léků   MeSH
• rostlinné extrakty chemie   MeSH
• rozpustnost MeSH
• sacharidové sekvence MeSH
• T-lymfocyty účinky léků   imunologie   patologie   MeSH
• TNF-alfa genetika   imunologie   MeSH
• voda MeSH
• xylosa chemie   izolace a purifikace   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11chighMHCII+ cells (Cnb1 CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3+ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11chighMHCII+ cells to express IL-2. Deleting IL-2 in CD11chighMHCII+ cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin-NFAT-IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.

• MeSH
• antigeny CD11c genetika   imunologie   MeSH
• buňky Th17 imunologie   MeSH
• geny MHC třídy II MeSH
• homeostáza MeSH
• interleukin-2 genetika   imunologie   MeSH
• kalcineurin genetika   imunologie   MeSH
• kolitida genetika   imunologie   MeSH
• lidé MeSH
• myeloidní buňky imunologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• střeva imunologie   MeSH
• Th1 buňky imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses.

• MeSH
• faktor stimulující granulocyto-makrofágové kolonie chemie   imunologie   metabolismus   MeSH
• HEK293 buňky MeSH
• infekce vyvolané poxviry imunologie   metabolismus   virologie   MeSH
• interakce hostitele a patogenu imunologie   MeSH
• interleukin-2 chemie   imunologie   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• multiproteinové komplexy chemie   imunologie   metabolismus   MeSH
• Parapoxvirus imunologie   metabolismus   MeSH
• vazba proteinů MeSH
• virové proteiny chemie   imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• glukany terapeutické užití   MeSH
• interleukin-2 * imunologie   MeSH
• kationické antimikrobiální peptidy * imunologie   MeSH
• kuchyňská sůl škodlivé účinky   MeSH
• lidé MeSH
• makrofágy patologie   MeSH
• regulační T-lymfocyty * MeSH
• Check Tag
• lidé MeSH

Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a "triggered exchange" mechanism favoring IL-2Rα(hi) Treg cells, creating a positive feedback loop for IL-2Rα(hi) cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ(hi) effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.

• MeSH
• autoimunitní nemoci imunologie   MeSH
• interleukin-2 chemie   genetika   imunologie   metabolismus   MeSH
• kompetitivní vazba účinky léků   MeSH
• lidé MeSH
• molekulární modely * MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• progrese nemoci MeSH
• proliferace buněk účinky léků   MeSH
• protilátky chemie   imunologie   farmakologie   MeSH
• průtoková cytometrie MeSH
• regulace genové exprese imunologie   MeSH
• regulační T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty - podskupiny cytologie   účinky léků   imunologie   MeSH
• terciární struktura proteinů MeSH
• vazba proteinů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Th17 cells express diverse functional programs while retaining their Th17 identity, in some cases exhibiting a stem-cell-like phenotype. Whereas the importance of Th17 cell regulation in autoimmune and infectious diseases is firmly established, the signaling pathways controlling their plasticity are undefined. Using a mouse model of invasive pulmonary aspergillosis, we found that lung CD103(+) dendritic cells (DCs) would produce IL-2, dependent on NFAT signaling, leading to an optimally protective Th17 response. The absence of IL-2 in DCs caused unrestrained production of IL-23 and fatal hyperinflammation, which was characterized by strong Th17 polarization and the emergence of a Th17 stem-cell-like population. Although several cell types may be affected by deficient IL-2 production in DCs, our findings identify the balance between IL-2 and IL-23 productions by lung DCs as an important regulator of the local inflammatory response to infection.

• MeSH
• alfa řetězce integrinu imunologie   MeSH
• Aspergillus imunologie   MeSH
• aspergilóza imunologie   patologie   MeSH
• buněčná diferenciace MeSH
• buňky Th17 imunologie   MeSH
• CD antigeny imunologie   MeSH
• dendritické buňky imunologie   MeSH
• interleukin-2 biosyntéza   imunologie   MeSH
• kalcineurin metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• plíce imunologie   mikrobiologie   patologie   MeSH
• transkripční faktory NFATC metabolismus   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γ(c) chain) and CD122 (β chain). However, the expression pattern and physiological role of IL-2 and IL-15 private receptor α chains CD25 and IL-15Rα, respectively, are strikingly different. CD25, together with CD122 and CD132, forms a trimeric high affinity IL-2 receptor that is expressed and functions on cells acquiring an IL-2 signal. Conversely, IL-15Rα is expressed and binds IL-15 with high affinity per se already in the endoplasmic reticulum of the IL-15 producing cells and it presents IL-15 to cells expressing CD122/CD132 dimeric receptor in trans. Thus, while IL-2 is secreted almost exclusively by activated T cells and acts as a free molecule, IL-15 is expressed mostly by myeloid cells and works as a cell surface-associated cytokine. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs; such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate the proliferation of a distinct population of immune cells, depending on the clone of the anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122(high) populations (memory CD8(+) T and NK cells) and intermediately also for CD25(high) populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25(high) cells. Although IL-2 immunocomplexes are much more potent than IL-2 in vivo, they show comparable to slightly lower activity in vitro. The in vivo biological activity of IL-15 can be dramatically increased through complexing with recombinant IL-15Rα-Fc chimera; however, IL-15/IL-15Rα-Fc complexes are significantly more potent than IL-15 both in vivo and in vitro. In this review we summarize and discuss the features and biological relevance of IL-2/anti-IL-2 mAbs and IL-15/IL-15Rα-Fc complexes, and try to foreshadow their potential in immunological research and immunotherapy.

• MeSH
• buňky NK cytologie   účinky léků   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• imunoglobuliny - Fc fragmenty chemie   MeSH
• imunokomplex genetika   imunologie   farmakologie   MeSH
• interleukin-15 genetika   imunologie   farmakologie   MeSH
• interleukin-2 genetika   imunologie   farmakologie   MeSH
• lidé MeSH
• monoklonální protilátky chemie   MeSH
• myši MeSH
• receptor interleukinu-15 - alfa-podjednotka genetika   imunologie   MeSH
• receptor interleukinu-2 - alfa-podjednotka genetika   imunologie   MeSH
• receptory interleukinů - společná gama-podjednotka genetika   imunologie   MeSH
• regulace genové exprese MeSH
• regulační T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH