11-21-2012, 06:41 PM
Cytokines belong to a class of regulatory proteins that are produced in very minute amounts upon stimulation and are generally pleiotropic in nature i.e. have multiple actions on different target cells or organs. They are potent molecules and some distinct cytokines have functions that are redundant and overlapping. The cytokines may be autocrine or paracrine having important role in the cross talk between the cells within the body. The advance in RDT has helped in grouping the cytokines and their receptors based on their structure by the cloning of their genes. The cytokine molecules, their receptors and their signal transduction pathways have become promising targets for the study of therapeutic interference due to the multifunctional nature of the cytokines.
The role of cytokines in the immune and inflammatory disorders has led to the advancement of the cytokine-based therapies. Manipulating the functions of the cytokines with the aim of either blocking or restoring the activity of the specific cytokines is one of the approaches in the cytokine therapies. The coupling of the cytokines with the toxins, cloning of the cytokines, formation and fusion of recombinant cytokines and its receptors with the Fc portion of the human IgG1and albumin for stabilizing and thus increasing the serum half-life of the proteins, are being studied. The cloning of the natural and synthetic antagonists that interfere in the ligand-receptor interaction is being studied. The use of gene therapy and antisense oligonucleotides in delivering cytokines is also being assessed. The currently used approach for cytokine therapy is the use of monoclonal antibodies (mAbs) for blocking or neutralizing the action of cytokines. The use of completely human anticytokine mAbs for clinical purpose has been approved.
A novel approach in the treatment of inflammatory autoimmune diseases is the targeting of inflammatory cytokines. The drugs that block their action e.g. TNF (Tumor Necrosis Factor) are being used successfully in therapeutics of rheumatoid arthritis (RA). Apart from it, the fusion proteins of the sTNF receptor and Interleukin (IL) 1R antagonist are also major components in the RA therapeutics. The therapy involving the TNF α and IL-1 antagonists are now having wider scope and their use is being extended to other autoimmune inflammatory diseases. The use of TNF blockers are much more efficient than the therapy aimed at only the antagonism of the IL-1. The successful studies on IL-1 have led to the development of mAbs that target some of the cytokines and their receptors such as IL-6, IL-8, IL-18 and Interferon γ in different clinical conditions. The cytokine therapy using recombinant cytokines has been successful in different cases such as
a) IL-2 in cancer
b) IFN-α and its derivatives in various types of viral infections and cancer
c) IFN-β in multiple sclerosis
d) IFN-γ in cancer and osteoporosis
e) IL-11 in post chemotherapy induced thrombocytopenia
In some cases, recombinant cytokines have produced no effect as seen in case of recombinant IL-10 that is immunosuppressive, however further research is required to analyse any possible therapeutic application in future. In rare cases, adverse side effects have been produced as seen in IL-12.
Autovaccination has been developed as a novel strategy for the therapy of various chronic diseases that result due to excess production of certain factors. The physical association of the foreign proteins with the self-antigens has been used for overcoming the tolerance against self-antigens. Successful studies have been performed in mice using immunologic complexes by chemical coupling of cytokines IL-9 and IL-12 that lead to the complete inhibition of the function of cytokines. Resistance for cutaneous leishmaniasis was seen in IL-9 vaccinated mice and for the experimental autoimmune encephalomyelitis (EAE) in the IL-12 vaccinated mice.
Application of cytokine therapy in different allergic diseases and asthma has shown great promise. Th2-dependent mechanisms mediate most of the allergic reactions in the body with the involvement of almost all the Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 making them potential targets for the cytokine therapy against allergic diseases. The main promoter of Th2 development is IL-4 in in-vivo and in-vitro as seen in murine models using OVA as the allergen. The role of IL-5 in allergic asthma is also being studied, though much success has not been achieved. Three anti-asthmatic drug leads in clinical phase I trials that are related to IL-13 demonstrate IL-13 to be a potential target for allergic asthma. Further studies are being conducted in mice to define the roles of IL-4 and IL-13 in different infectious and allergic diseases by using knockout models.
The pleiotropic nature of the cytokines remains to be a drawback in the application of cytokine therapy for complex diseases. Hence, if experiments could be designed for the simultaneous inactivation or activation of multiple cytokines, then complex disorders could be treated with this therapy. RNA interference could help in achieving this goal in future due to the advancement in RNAi delivery studies.
The role of cytokines in the immune and inflammatory disorders has led to the advancement of the cytokine-based therapies. Manipulating the functions of the cytokines with the aim of either blocking or restoring the activity of the specific cytokines is one of the approaches in the cytokine therapies. The coupling of the cytokines with the toxins, cloning of the cytokines, formation and fusion of recombinant cytokines and its receptors with the Fc portion of the human IgG1and albumin for stabilizing and thus increasing the serum half-life of the proteins, are being studied. The cloning of the natural and synthetic antagonists that interfere in the ligand-receptor interaction is being studied. The use of gene therapy and antisense oligonucleotides in delivering cytokines is also being assessed. The currently used approach for cytokine therapy is the use of monoclonal antibodies (mAbs) for blocking or neutralizing the action of cytokines. The use of completely human anticytokine mAbs for clinical purpose has been approved.
A novel approach in the treatment of inflammatory autoimmune diseases is the targeting of inflammatory cytokines. The drugs that block their action e.g. TNF (Tumor Necrosis Factor) are being used successfully in therapeutics of rheumatoid arthritis (RA). Apart from it, the fusion proteins of the sTNF receptor and Interleukin (IL) 1R antagonist are also major components in the RA therapeutics. The therapy involving the TNF α and IL-1 antagonists are now having wider scope and their use is being extended to other autoimmune inflammatory diseases. The use of TNF blockers are much more efficient than the therapy aimed at only the antagonism of the IL-1. The successful studies on IL-1 have led to the development of mAbs that target some of the cytokines and their receptors such as IL-6, IL-8, IL-18 and Interferon γ in different clinical conditions. The cytokine therapy using recombinant cytokines has been successful in different cases such as
a) IL-2 in cancer
b) IFN-α and its derivatives in various types of viral infections and cancer
c) IFN-β in multiple sclerosis
d) IFN-γ in cancer and osteoporosis
e) IL-11 in post chemotherapy induced thrombocytopenia
In some cases, recombinant cytokines have produced no effect as seen in case of recombinant IL-10 that is immunosuppressive, however further research is required to analyse any possible therapeutic application in future. In rare cases, adverse side effects have been produced as seen in IL-12.
Autovaccination has been developed as a novel strategy for the therapy of various chronic diseases that result due to excess production of certain factors. The physical association of the foreign proteins with the self-antigens has been used for overcoming the tolerance against self-antigens. Successful studies have been performed in mice using immunologic complexes by chemical coupling of cytokines IL-9 and IL-12 that lead to the complete inhibition of the function of cytokines. Resistance for cutaneous leishmaniasis was seen in IL-9 vaccinated mice and for the experimental autoimmune encephalomyelitis (EAE) in the IL-12 vaccinated mice.
Application of cytokine therapy in different allergic diseases and asthma has shown great promise. Th2-dependent mechanisms mediate most of the allergic reactions in the body with the involvement of almost all the Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 making them potential targets for the cytokine therapy against allergic diseases. The main promoter of Th2 development is IL-4 in in-vivo and in-vitro as seen in murine models using OVA as the allergen. The role of IL-5 in allergic asthma is also being studied, though much success has not been achieved. Three anti-asthmatic drug leads in clinical phase I trials that are related to IL-13 demonstrate IL-13 to be a potential target for allergic asthma. Further studies are being conducted in mice to define the roles of IL-4 and IL-13 in different infectious and allergic diseases by using knockout models.
The pleiotropic nature of the cytokines remains to be a drawback in the application of cytokine therapy for complex diseases. Hence, if experiments could be designed for the simultaneous inactivation or activation of multiple cytokines, then complex disorders could be treated with this therapy. RNA interference could help in achieving this goal in future due to the advancement in RNAi delivery studies.
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