Complement is a fundamental component of the innate

Complementis a fundamental component of the innate immunity, which has been known formany years to be involved in the recognition and elimination of invadingpathogens. Complement system is a key player of humoral immunity and participatesin largely diverse processes, such as clearance of immune complexes,mobilization of hematopoietic stem-progenitor cells, control of adaptiveimmunity and angiogenesis.

The complement regulatory proteins (CRPs) optimizethe effect of complement and avoid excessive cell lysis. However, in cancerpatients, membrane complement regulatory proteins (mCRPs) have been reported tobe highly expressed in some cancer types on the surface of neoplastic cells. Hence,they act as a major barrier for complement dependent cytotoxicity mediated bytherapeutic anticancer monoclonal antibodies especially in leukemia. The aim ofthe current study is investigate the effect of CD46; a membrane complementregulatory protein on tumor pathogenesis in Egyptian leukemia patients. Thestudy will be assessing the level of expression of CD46 in blood samples ofleukemia patients compared to healthy controls. Antisense short interfering RNA(siRNA) will be applied to knock down the expression of CD46 with the aim of exploitingsuch approach for reducing complement resistance of neoplastic cells on Rajiand REH tumor cell. Due to the clinical applicability of siRNA, the anti-senseapproach that will be used in this study may offer an additional alternative toenhance the efficacy of antibody- and complement-based cancer immunotherapy.

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Keywords:Complement,cancer, leukemia, complements regulatory proteins, CD46, immunotherapy.Introduction:Thecomplement system is a central part of the innate immune response. It acts as        a first defense mechanism against invasivemicroorganisms. It regulates the coagulation system and cell to cellcommunications. It is also involved in angiogenesis and regeneration of tissues.The complement system coordinates between the innate and adaptive immunity. Itincreases the ability of phagocytic cells and antibodies to clear microbes anddamaged cells from an organism, promotes inflammation, and attacks the plasmamembrane of the pathogen 1,2. For decades, complement has beenrecognized as an effector arm of the immune system that contributes to thedestruction of tumor cells.

In fact, many therapeutic strategies have beenproposed that are based on the intensification of complement-mediated responsesagainst tumors. Despite substantial advances in the chemotherapeutic managementof cancer, more than half of all cancer patients do not respond to therapy orrelapse, dying from metastatic disease. Alternatively, cancer therapiesdirected at immune modulation have also been pursued, but with only modestadvances to date. Regulationof the complement activation is very crucial to keep the homeostasis of anorganism. Complement regulators are divided into two groups; soluble andmembrane-bound proteins.

These complement regulatory proteins (CRPs) controlinappropriate complement attack if produced in normal amounts. Membranecofactor protein (CD46), decay-accelerating factor (CD55), and CD59 (protectin)are examples of membrane-bound complement regulatory proteins (mCRPs) 3.They control the complement activation at the level of C3. CD46 controlscleavage of C3b and C4b, while CD55 causes C3/C5 convertases decay. CD59 workson the terminal step of complement activation where it binds to C9 and hence,prevents membrane attack complex (MAC) assembly. This inhibits the complementdependent cytotoxicity (CDC) 4.  Severalstudies have proven that membrane-bound complement regulatory proteins (mCRPs)are overly expressed in neoplastic cells, which is a reason why the efficacy ofcancer-immunotherapy with complement-activating monoclonal antibodies islimited 4,5.

CD46 is an intrinsic complement inhibitor widelydistributed among leukocytes, endothelial cells, and epithelia but absent onerythrocytes. Its structure consists of four short consensus repeats (SCR): aserine/threonine-rich region (ST), a sequence of unknown significance (UK), atransmembrane domain (TM) and a 16 or 23 amino acid cytoplasmic tail (CYT). Itirreversibly binds C3b and C4b where it acts as a cofactor for the plasmaserine protease factor I 5. According to previous studies, thelevel of expression of mCRPs in neoplastic cells differs according to the typeof tumor, where in some tumors of the ductal carcinoma of the breast only oneof the three mCRPs was highly expressed, while in other tumors all three wereexpressed.

In colon carcinoma, all three were found to be highly expressed andin non-small cell carcinoma of the lung, both CD46 and CD59 were highlyexpressed whereas CD55 had a variable level of expression 6. Previousstudies used different approaches to neutralize the mCRPs as use of antibodiesthat block their effect and using cytokines to downregulate mCRPs expression 4.A better understanding of the molecular interactions between tumors and theimmune system should lead to better anticancer therapies.

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