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Effects of Type 1 Diabetes

Discuss about the Novel Therapeutic Strategy for Autoimmune Diseases.

Immunotherapy, also termed as biologic therapy is a form of cancer treatment that bolsters the body’s natural defenses in order to fight cancer. Immunotherapy functions by augmenting the immune system to enable its improved functioning in destroying cancer cells, precluding the spread of cancer to other body parts and preventing or reducing the growth of cancer cells (Rosenberg, Yang, and Restifo, 2004). In this research paper, two conditions- cancer and autoimmune diseases are considered. An autoimmune disease occurs when one’s immune system erroneously attacks the body. For cancer, there are varied factors which aid in tumor persistence. Immune-editing is one such factor which aids the tumors to evade the surveillance of the host’s immunity hence the tumours may lie dormant within the patient for long periods via senescence and equilibrium before they re-emerge. This research paper thus appraises the commonly used immunotherapies for cancer and autoimmune disease such as type 1 diabetes treatment, as well as the solutions for immunotherapy improvements.

Taking into concerns of the effects of type 1 diabetes which is T cell autoimmune disease that lead to altered glucose and homeostasis, plus severe reduction of insulin due to the destruction of beta cells in the islets the regulatory T cells and effector T cells are considered to be the major components that lead to autoimmunity (Yu, Paiva and Flavell, 2017). Due to that reason, structures have been put into trials to in order to try to boost the functions of the regulatory T cells and at the same time reducing the effects of the effector T cells (Yu, Paiva and Flavell, 2017).  The FoxP3+T cell regulator and the Trl may have different functions in the control of diabetes. The combination of the both has shown to lead to extrinsic and intrinsic prevention of Type 1 Diabetes. The Trl has demonstrated to suppress the IL-1 beta production and inflammatory NLrp3 activation. The Trl usually serve as an immunologic biomarker that usually helps when differentiating people at risk of developing type 1 diabetes thus it can help in predicting the outcomes (Yu, Paiva and Flavell, 2017). Several clinical trials have been conducted on using the anti-CD28 antibody in examining the effects and dangers of injecting agents that exert specific effects of T cell functions in vivo which have designed to target specifically the T cells regulators. However, none of both the in vivo and in vitro modulations have induced a long-lasting beta cells protection (Yu, Paiva and Flavell, 2017). This is due to the fact that T cells regulate immunotherapy can be induced by several factors. Firstly, the T cells regulators in adults diagnosed between 14-104 weeks is less effective compared to children diagnosed within the first two months of diagnosis.  Therefore the initial C peptide serum and the disease duration might determine the success of the treatment (Yu, Paiva and Flavell, 2017).  (Yu, Paiva and Flavell, 2017) Therapeutic approach that has been used to modulate regulatory T cells

Anti-CD28 Antibody Clinical Trials

The most significant goal of the immunotherapy is the induction of tolerance. This has been demonstrated recently by using anti-CD3 monoclonal antibodies which have shown promise in clinical trials which has autoimmune diseases in animal models (Kuhn and Weiner, 2016).The induction of the tolerance of anti-CD3 mAbs is directly related to Tregs that normally control pathogenic autoimmune responses. The anti-CD3 normally binds to the CD3/TCR complex which normally leads to modulation of antigens. This means that the Anti-CD3 binding lead to the shedding of the CD3/TCR from the cell surface which in turn makes the T cells blind toward their cognate antigens (Kuhn and Weiner, 2016). The anti-CD3 mAb induction can usually lead to other reactions and processes to happen at the same time using the CD3/TCR complex like inducing cell death and T cell anergic. Additionally, TGF-beta that normally promotes a tumorigenic microenvironment is produced by both macrophages and apoptotic T cells that ingest apoptotic cell bodies (Kuhn and Weiner, 2016). The CD4+ T cells become suppressive when the FoxP3 in them is induced by TGF-beta. The effector T cells are inhibited by both CD4+FoxP3+ and TGF-beta thus skewing antigen presenting cells toward tolerogenic phenotype (Kuhn and Weiner, 2016).                       

The dendritic cells(DC) immunotherapy for cancer has been commonly used and it is also in clinical trials especially in cancer of the intestines. Dendritic cells normally phagocyte microbes which are crossing the thin epithelial barriers in the intestines (Kuhn and Weiner, 2016). There are various stages of activation of the dendritic cells. During their process of maturation, TH17 cells are induced by the IL-6 and TGF-beta (Srivastava and Riddell, 2018). The proinflammatory mediators of neutrophils chemotaxis including the IL-17 and IL-22 are secreted by the TH17 thus leading to stimulation of secretion of antimicrobial molecules and epithelial homeostasis. The activity of sub epithelial phagocytes is activated by IFNy secreted by TH1 which is normally induced by dendritic cells (Srivastava and Riddell, 2018). In a tumour the TH17 cells are attracted by the tumour microenvironment chemokines (Kuhn and Weiner, 2016). These cells are expanded by the reactions of the dendritic cells through the secretion of IL1 and IL23. Therefore the TH17 cells end up promoting trafficking and retention of natural killers and CD8+T cells in the microenvironment of a tumor. This happens through the production of CXCL 10  and CHCL produced by the tumor cells (Kuhn and Weiner, 2016). At the same time the dendritic cells are expressed through the process of CCL20 stimulation by the TH17 and thus CCR6 are recruited. Generally the TH17 fight cancer cells by inducing the pro-antiinflammatory effector cells recruitment which includes dendritic cells, natural killers, and the cytotoxic T cells (Srivastava and Riddell, 2018).

Immunotherapy using Genetically Modified T Cells

The immunotherapy using the T cells that are genetically modified to express chimeric Ag receptors(CARs) that specifically target tumors associated cells have demonstrated to be efficient when dealing with hematological malignancies (Weiden, Tel and Figdor, 2017). This approach can be used to treat various epithelial malignancies that consist of the majority of cancer cases which evade most of the immunological attack through the different submissive mechanism. The CAR T cells trafficking usually is of dependant on receptors expression of chemokines that are released by the tumors. The CXCR2 and CCR5 chemokines receptors are originally expressed by the CAR T cells. CAR T cells can be modified in order to express receptors such as CCR2 and CCR4 which are chemokines naturally secreted thus improving trafficking to those tumors. The TME upregulatory expression due to the inhibitory receptors that are brought by the Ag-activated CAR T cells can lead to T cells dysfunctions (Weiden, Tel and Figdor, 2017). The T cells can be inhibited directly or indirectly by the factors such as potassium, adenosine and reactive oxygen species (ROS) which are normally found in the tumor microenvironment(TME). Therefore by overcoming the immunosuppressive cells in the TME can bring significant results in CAR T-cells efficiency. Reducing the activity of Tregs and MDSCs through genetic modification have demonstrated to improve the efficiency of T cell therapy in clinical trials. Cancer-associated fibroblasts (CAFs) that play a high level of fibroblast activation and are normally in stromal tumor cells can play a major role in developing a microenvironment that is immunosuppressive by limiting the T cells penetration through deposition of extracellular matrix proteins (Weiden, Tel and Figdor, 2017). Therefore targeting the CAFs with fibrinogen activation proteins specific to CAR T cells in order to secrete extracellular matrix-degrading enzymes can increase their activities to filtrate and lyse tumors (Weiden, Tel and Figdor, 2017).


The B cell malignancies have demonstrated a success in CAR T cell immunotherapy. The CAR T cells have shown to be able to target the B cell lineage-specific markers which include the CD19, CD22 and the CD22 which are normally not expressed in other tissues. Specifically, the CD19 which is highly expressed as it has a high level of expression in B cell tumors. The results after treatment normally consist of plasma cells and later the humoral immunity which is necessary. However, the CAR T cells efficiency has also lead to toxicity in terms of tumor burden and proliferative rates. More severe syndrome even greater than the influenza syndromes is commonly observed in TIL and TCR based therapies.

Since currently there is no tumor specificity inherent to tumours associated antigens (TAAs) the desired cancer vaccine strategy addressing the concept where various multiple neoantigens that are a tumor-specific is recommended (Hu, Ott and Wu, 2017). However, only recently the discovering of personal antigens have been included in real time therapy. Furthermore, the clinical use of TAAs that are expressed in a particular type of cancer per a given tumor type has led to the development and focusing on tumor antigens that have similarity with shared expressions across malignant such as NY-ESO and MAGEI (Hu, Ott and Wu, 2017).  Studies have proved that there is high evidence of similar genetic characteristics of tumor cell of the people with the same type of tumors and also in the individual tumors. However, due to complexity of HLA molecules tumor antigens peptides from a different individual may be fairly different. In addition to that vaccines that target single tumours have been found to be not adequate enough in the therapy of genetic related tumours due to clonal evolution (Hu, Ott and Wu, 2017).

Currently, the development of antibody drugs conjugates(ADC) has benefited from the overall mAbs therapeutic designs improvements and from enhancing homogeneity in order to pomote specific methods for conjugate synthesis (Beck et al., 2017). Warheads and diversification of combining strategies have created new opportunities in order to improve drug delivery in tumors and the same time reducing drugs exposure to normal tissues (Beck et al., 2017). This has lead to more understanding of determining the toxicity of one drug and toxicity when combined with others in the therapies. In order to increase the therapeutic index od ADCs, various improvements have been developed by either minimizing the effect of the minimum doses or by increasing the selectivity of ADCs to the maximum doses (Beck et al., 2017). The effects and characteristics of more effective ADCs have been developed in order to control the macromolecular structures. Protein structural characterization tools are being used to determine the therapeutic success of the next generation ADCs biotransformation in vivo. For example, several ADCs that target hepatic toxicities have been found due to their mannose receptors expression on the cell surface of the hepatocytes (Beck et al., 2017). This concludes that antibodies that should be selected in the next generation ADCs should have low cell surface mannose receptors. Other examples that are being observed in clinical trials include alternatives for maleimide conjugations that are normally in the second class of ADCs (Beck et al., 2017).The product quality of both small molecule components and biological components are being considered when developing ADCs due to their hybrid nature. Therefore, early development and assessment have been focusing on their structural characteristics. In addition to that, recent developed ADCs have been focused on the provision of products with acceptable cytotoxicity (Beck et al., 2017). This, in turn, will lead to the development of ADCs with the likelihood of having warheads with strategic mechanisms of actions. Moreover, proteins scaffolds which are alternatives of mAbs are being investigated at clinical stages (Beck et al., 2017).

DCs are recognized as “Nature’s adjuvants” and are the most effective APCs since they can activate both memory and naïve immune responses. Tolerogenic dendritic cells (tolDCs) are an equally promising therapeutic tool for the restoration of immune tolerance for autoimmune conditions. DCs have the ability of precisely targeting pathogenic T-cell and leave other defensive T cell responses unharmed (Kracht, Zaldumbide, and Roep, 2016). DCs are also the choicetolerogenic cells which can restore immune tolerance in Type 1 Diabetes as a potentially efficacious and safe immunotherapy.  As Kracht, Zaldumbide, and Roep, (2016) observe, Type 1 diabetes is described by its discriminatory and progressive annihilation of beta cells that secrete insulin in the immune system. DC cells are preferred for this role since they are natural migratory and can also be generated easily from the blood.

For cancer cells, cytotoxic T cells are the powerful destroyers of the cancer cells. Unfortunately, CD4, as well as CD8 TILs, are more likely to be suppressed thus cannot control the growth of tumors. The prospect of cancer immune therapy hinges on the amalgamation of select cancer serums as well as checkpoint inhibitors. Therefore, it is possible to reduce the requirements for useful antitumor immunity by obstructing inhibitory receptors like CTLA4 and PD-1 (Bousquet and Demoly, 2006). Nevertheless, there is little knowledge presently on how the majority of the inhibitory receptors which are targeted by checkpoint inhibitors operate. These particles operate by down-regulating cell signals at immune synapse but the mechanism of how this happens is not understood. Gaining this knowledge will elucidate more information on regulatory pathways as well as those of common signaling and thus more controlled targets for pharmacological interventions will be possible. Achieving selective immunization for antitumor responses with the application of cancer vaccines will also be possible.

Conclusion

In conclusion, the application of immunotherapy to address cancer is rapidly advancing. Through such applications, lives have been saved and improved. This include use of immunotherapies such as monoclonal antibodies, non-specific immunotherapies such as antigen non-specific T-cell activation, T cell therapy, oncolytic virus therapy, innate immunity activation and the use of cancer vaccines. The fact that different cancers bear unique immunological fingerprints makes it difficult to address the concerns passed by these conditions. The main challenge with cancer control and eradication lies in promoting effectual promotion of cancer immunity while excluding the associated toxic side effects that come with autoimmune conditions. Overreliance on non-specific immunosuppressive drugs has been long hence effectual immunotherapy achievable by targeted desensitization where allergy linked antigens must now be considered.  Antigen-specific immunotherapies will herald a new era in addressing these diseases.

References

Bousquet, J. and Demoly, P., 2006. Specific immunotherapy–an optimist future. Allergy, 61(10), pp.1155-1158.

Beck, A., Goetsch, L., Dumontet, C. and Corvaïa, N. (2017). Strategies and challenges for the next generation of antibody–drug conjugates. Nature Reviews Drug Discovery, 16(5), pp.315-337.

Caspi, R.R., 2008. Immunotherapy of autoimmunity and cancer: the penalty for success. Nature reviews immunology, 8(12), p.970.

Dixit, A., Tanaka, A., Greer, J.M. and Donnelly, S., 2017. Novel Therapeutics for Multiple Sclerosis Designed by Parasitic Worms. International journal of molecular sciences, 18(10), p.2141.

Jansen, M.A., Spiering, R., Broere, F., van Laar, J.M., Isaacs, J.D., van Eden, W. and Hilkens, C.M., 2017. Targeting of tolerogenic dendritic cells towards heat shock proteins: a novel therapeutic strategy for autoimmune diseases? Immunology.

Hu, Z., Ott, P. and Wu, C. (2017). Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nature Reviews Immunology, 18(3), pp.168-182.

Kuhn, C. and Weiner, H. (2016). Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy, 8(8), pp.889-906.

Kracht, M.J., Zaldumbide, A. and Roep, B.O., 2016. Neoantigens and microenvironment in type 1 diabetes: lessons from antitumor immunity. Trends in Endocrinology &Metabolism, 27(6), pp.353-362.

Kracht, M.J., Zaldumbide, A. and Roep, B.O., 2016. Neoantigens and microenvironment in type 1 diabetes: lessons from antitumor immunity. Trends in Endocrinology &Metabolism, 27(6), pp.353-362.

Kuhn, C. and Weiner, H.L., 2016. Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy, 8(8), pp.889-906.

Mandal, A. and Viswanathan, C., 2015. Natural killer cells: in health and disease. Hematology/oncology and stem cell therapy, 8(2), pp.47-55.

Rosenberg, S.A., Yang, J.C. and Restifo, N.P., 2004. Cancer immunotherapy: moving beyond current vaccines. Nature medicine, 10(9), p.909.

Srivastava, S. and Riddell, S. (2018). Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. The Journal of Immunology, 200(2), pp.459-468.

Varyani, F., Fleming, J.O., and Maizels, R.M., 2017. Helminths in the gastrointestinal tract as modulators of immunity and pathology. American Journal of Physiology-Gastrointestinal and Liver Physiology, 312(6), pp. G537-G549.

Weiden, J., Tel, J. and Figdor, C. (2017). Synthetic immune niches for cancer immunotherapy. Nature Reviews Immunology, 18(3), pp.212-219.

Yu, H., Paiva, R. and Flavell, R. (2017). Harnessing the power of regulatory T-cells to control autoimmune diabetes: overview and perspective. Immunology, 153(2), pp.161-170.

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