Immunological effects of adjuvants, their mechanisms, and relevance to vaccine safety

The purpose of this review is to provide a general overview of ad-juvants as immune potentiators, and to offer new insights into the immunological basis and molecular mechanisms of their action. Adju-vants are a key component of many vaccines and their use and development enables many avenues of vaccine design that would otherwise be impossible. Nevertheless, adjuvants are often associated with many safety concerns. Search of available medical literature on adjuvants, vaccines, and their mechanisms of action was performed. Additional articles were identified based on citations in retrieved articles. The main role of adjuvants is to trick the immune system in perceiving vaccine antigen as a serious threat, and thus initiate innate and consec-utively adaptive response mechanisms, including long-term immune memory to that antigen. Adjuvants do that by triggering the same evolutionary conserved mechanisms that innate immunity utilizes to detect danger. By inducing innate immune reaction, adjuvants can concurrently provoke some undesirable immune response. However, serious adverse reactions to adjuvanted (as well as nonadjuvanted) vaccines are extremely rare, and there are carefully elaborated regulatory mechanisms to ensure that risks of such adverse reactions are kept at minimum. Conclusion. The use of adjuvants allows a great variety of vaccine designs, enabling the development of safer, more effective, more optimized, and more accessible vaccines than it would be possible without adjuvants. Despite frequent calls to debate, all currently used adjuvanted vaccines have repeatedly demonstrated an excellent safety profile and remain one of the principal tools of science-based medicine in preventing infectious diseases

Transforming growth factor-beta1 and myeloid-derived suppressor cells: A cancerous partnership

Transforming growth factor-beta1 (TGF-beta 1) plays a crucial role in tumor progression. It can inhibit early cancer stages but promotes tumor growth and development at the late stages of tumorigenesis. TGF-beta 1 has a potent immunosuppressive function within the tumor microenvironment that largely contributes to tumor cells' immune escape and reduction in cancer immunotherapy responses. Likewise, myeloid-derived suppressor cells (MDSCs) have been postulated as leading tumor promoters and a hallmark of cancer immune evasion mechanisms. This review attempts to analyze the prominent roles of both TGF-beta 1 and MDSCs and their interplay in cancer immunity. Furthermore, therapies against either TGF-beta 1 or MDSCs, and their potential synergistic combination with immunotherapies are discussed. Simultaneous TGF-beta 1 and MDSCs inhibition suggest a potential improvement in immunotherapy or subverted tumor immune resistance

Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs’ osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration

Estramustine Phosphate Inhibits TGF-beta-Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production

Transforming growth factor-beta (TGF-beta) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF-beta regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF-beta-induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-beta. Moreover, EP greatly reduced the capacity of TGF-beta to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF-beta-induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-beta

Effects of interleukin-17 on mouse bone marrow-derived mesenchymal stem cells in vitro

Mezenhimske matične ćelije (MSC) pripadaju populaciji multipotentnih adultnih matičnih ćelija koje se nalaze u mnogim tkivima gde ostvaruju važne uloge u održavanju homeostaze. Zahvaljujući višestrukom potencijalu u regeneraciji tkiva, regulaciji hematopoeze i imunomodulaciji, kao i relativno lakoj dostupnosti iz raznih adultnih i perinatalnih tkiva, intenzivirana su istraživanja kako osnovne biologije MSC, tako i ona usmerena ka mogućnosti njihove terapijske primene. Iako je u poslednjoj deceniji došlo do značajnog i brzog napretka u razumevanju njihove prirode, raznovrsnih funkcija i mehanizama njihovog delovanja, još smo daleko od rasvetljavanja nekih osnovnih pitanja ključnih za njihovu efikasnu i bezbednu kliničku primenu. Poslednjih godina se sve više uviđa značaj lokalne mikrosredine u usmeravanju MSC ka obavljanju mnogobrojnih i često suprotstavljenih funkcija. Interleukin-17 (IL-17) je plejotropni citokin sa značajnim ulogama u mnogim fiziološkim i patološkim procesima organizma, poput inflamacije, imunskog odgovora i regulacije hematopoeze. IL-17 svoje efekte ostvaruje uglavnom indirektno, delujući na stromalne ćelije, modulišući u njima ekspresiju različitih solubilnih i membranskih faktora. Iako su istraživanja uticaja IL-17 na proliferaciju i diferencijacju humanih i mišjih MSC započeta, mnogi efekti, poput uticaja na regulatornu ulogu ovih ćelija u hematopoezi i imunskom odgovoru, kao i mehanizmi i značaj njegovog delovanja na MSC, još nisu dovoljno ispitani. Cilj ovog istraživanja bio je da se izoluju i okarakterišu MSC iz kostne srži miša (mBM-MSC) i utvrdi efekat IL-17 na fenotipske karakteristike, sposobnost višelinijske diferencijacije, proliferaciju, kapacitet podržavanja hematopoeze i imunomodulatorne sposobnosti ovih ćelija. Takođe, ispitivani su i mehanizami delovanja IL-17 na 8 mBM-MSC, uključujući aktivaciju signalnih puteva i ulogu NO kao posrednika u ovim efektima...Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are found in many tissues where they play an important role in maintaining the tissue homeostasis. Due to their enormous potential in tissue regeneration, regulation of hematopoiesis, and immunomodulation, as well as the fact that they are readily available from numerous adult and perinatal tissues, MSCs have been in the focus of basic and clinical research in the last few decades. Although a significant and rapid progress in understanding the nature, various functions, and mechanisms of action of MSCs has been made during the last decade, we are still far from resolving some of the key issues that are necessary for their effective and safe use in the clinics. The importance of the local microenvironment in directing MSCs to perform their numerous and often conflicting functions have been increasingly recognized over the recent years. Interleukin-17 (IL-17) is a pleiotropic cytokine with important roles in many physiological and pathological processes, such as inflammation, immune response, and regulation of hematopoiesis. This cytokine achieves its functions indirectly, by modulating the expression of variety of soluble and membrane-bound factors in stromal cells. Although some effects of IL-17 on the proliferation and differentiation of MSCs have been demonstrated in human and mouse models, other potential effects, such as the influence of this cytokine on the regulatory role of MSCs in hematopoiesis and immune response, as well as the mechanisms and the significance of its action, are not sufficiently elucidated. The aim of this study was to isolate and characterize MSCs from mouse bone marrow (mBM-MSCs) and to analyze the effects of IL-17 on their phenotype, multilineage differentiation, proliferation, hematopoietic supportive capacity, and immunomodulatory activity. The mechanisms of action, including the signaling pathways and the role of NO as a mediator, were also examined..

The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies

Uticaj interleukina-17 na mezenhimske matične ćelije kostne srži miša u in vitro uslovima

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are found in many tissues where they play an important role in maintaining the tissue homeostasis. Due to their enormous potential in tissue regeneration, regulation of hematopoiesis, and immunomodulation, as well as the fact that they are readily available from numerous adult and perinatal tissues, MSCs have been in the focus of basic and clinical research in the last few decades. Although a significant and rapid progress in understanding the nature, various functions, and mechanisms of action of MSCs has been made during the last decade, we are still far from resolving some of the key issues that are necessary for their effective and safe use in the clinics. The importance of the local microenvironment in directing MSCs to perform their numerous and often conflicting functions have been increasingly recognized over the recent years. Interleukin-17 (IL-17) is a pleiotropic cytokine with important roles in many physiological and pathological processes, such as inflammation, immune response, and regulation of hematopoiesis. This cytokine achieves its functions indirectly, by modulating the expression of variety of soluble and membrane-bound factors in stromal cells. Although some effects of IL-17 on the proliferation and differentiation of MSCs have been demonstrated in human and mouse models, other potential effects, such as the influence of this cytokine on the regulatory role of MSCs in hematopoiesis and immune response, as well as the mechanisms and the significance of its action, are not sufficiently elucidated. The aim of this study was to isolate and characterize MSCs from mouse bone marrow (mBM-MSCs) and to analyze the effects of IL-17 on their phenotype, multilineage differentiation, proliferation, hematopoietic supportive capacity, and immunomodulatory activity. The mechanisms of action, including the signaling pathways and the role of NO as a mediator, were also examined...Mezenhimske matične ćelije (MSC) pripadaju populaciji multipotentnih adultnih matičnih ćelija koje se nalaze u mnogim tkivima gde ostvaruju važne uloge u održavanju homeostaze. Zahvaljujući višestrukom potencijalu u regeneraciji tkiva, regulaciji hematopoeze i imunomodulaciji, kao i relativno lakoj dostupnosti iz raznih adultnih i perinatalnih tkiva, intenzivirana su istraživanja kako osnovne biologije MSC, tako i ona usmerena ka mogućnosti njihove terapijske primene. Iako je u poslednjoj deceniji došlo do značajnog i brzog napretka u razumevanju njihove prirode, raznovrsnih funkcija i mehanizama njihovog delovanja, još smo daleko od rasvetljavanja nekih osnovnih pitanja ključnih za njihovu efikasnu i bezbednu kliničku primenu. Poslednjih godina se sve više uviđa značaj lokalne mikrosredine u usmeravanju MSC ka obavljanju mnogobrojnih i često suprotstavljenih funkcija. Interleukin-17 (IL-17) je plejotropni citokin sa značajnim ulogama u mnogim fiziološkim i patološkim procesima organizma, poput inflamacije, imunskog odgovora i regulacije hematopoeze. IL-17 svoje efekte ostvaruje uglavnom indirektno, delujući na stromalne ćelije, modulišući u njima ekspresiju različitih solubilnih i membranskih faktora. Iako su istraživanja uticaja IL-17 na proliferaciju i diferencijacju humanih i mišjih MSC započeta, mnogi efekti, poput uticaja na regulatornu ulogu ovih ćelija u hematopoezi i imunskom odgovoru, kao i mehanizmi i značaj njegovog delovanja na MSC, još nisu dovoljno ispitani. Cilj ovog istraživanja bio je da se izoluju i okarakterišu MSC iz kostne srži miša (mBM-MSC) i utvrdi efekat IL-17 na fenotipske karakteristike, sposobnost višelinijske diferencijacije, proliferaciju, kapacitet podržavanja hematopoeze i imunomodulatorne sposobnosti ovih ćelija. Takođe, ispitivani su i mehanizami delovanja IL-17 na 8 mBM-MSC, uključujući aktivaciju signalnih puteva i ulogu NO kao posrednika u ovim efektima..

Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression

Transforming growth factor-beta (TGF-beta) and oxidative stress/ReactiveOxygen Species (ROS) both have pivotal roles in health and disease. In this review we are analyzing the interplay between TGF-beta and ROS in tumorigenesis and cancer progression. They have contradictory roles in cancer progression since both can have antitumor effects, through the induction of cell death, senescence and cell cycle arrest, and protumor effects by contributing to cancer cell spreading, proliferation, survival, and metastasis. TGF-beta can control ROS production directly or by downregulating antioxidative systems. Meanwhile, ROS can influence TGF-beta signaling and increase its expression as well as its activation from the latent complex. This way, both are building a strong interplay which can be taken as an advantage by cancer cells in order to increment their malignancy. In addition, both TGF-beta and ROS are able to induce cell senescence, which in one way protects damaged cells fromneoplastic transformation but alsomay collaborate in cancer progression. The mutual collaboration of TGF-beta and ROS in tumorigenesis is highly complex, and, due to their differential roles in tumor progression, careful consideration should be taken when thinking of combinatorial targeting in cancer therapies

Interleukin-17 and Its Implication in the Regulation of Differentiation and Function of Hematopoietic and Mesenchymal Stem Cells

Adult stem cells have a great potential applicability in regenerative medicine and cell-based therapies. However, there are still many unresolved issues concerning their biology, and the influence of the local microenvironment on properties of stem cells has been increasingly recognized. Interleukin (IL-) 17, as a cytokine implicated in many physiological and pathological processes, should be taken into consideration as a part of a regulatory network governing tissue-associated stem cells' fate. This review is focusing on the published data on the effects of IL-17 on the properties and function of hematopoietic and mesenchymal stem cells and trying to discuss that IL-17 achieves many of its roles by acting on adult stem cells