Work with LifeSpan to design a custom immunohistochemistry to address your specific biological question. Outsource the entire localization process without having to worry about finding and characterizing target specific antibodies, sourcing and validating difficult-to-find tissues, and having the ability to interpret the resulting immunostaining in relation to complex human pathologies.TCR Screening Services
Test your therapeutic antibodies in immunohistochemistry against a broad panel of normal frozen human tissue types in order to determine potential unintended binding. Our non-GLP TCR services are designed on the FDA recommendation outlined in their "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use".
Cytokines are small proteins produced in the body to mediate cell signaling. Most, but not all, cytokines are involved in regulation of the immune system. Cytokine Release Syndrome is characterized by an immune over-response, where the majority of the damage done to the host is due to the immune system rather than the pathogen. This damage is mediated by excessive recruitment of immune cells to the sites of infection and overproduction of inflammatory cytokines, which lead to tissue damage and hypotensive shock.
Both severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause a severe and highly lethal respiratory disease in humans. This disease is characterized by a prominent pro-inflammatory response and mediated by release of cytokines. (Chan, J. F, 2015)
COVID-19 induces pro-inflammatory generation and secretion of cytokines, including IL-1b and IL-6, via the toll like receptors (TLR). This causes the production of active mature IL-1b, which is a mediator of lung inflammation, fever and fibrosis. Anti-inflammatory cytokines, such as IL1-Ra, IL-37 or IL-38 could potentially provide relief in both systemic inflammation and fever occurring after infection (Conti. P, 2020).
Cytokines involved in infection from SARS-CoV-2 include IL-1, IL-1B, IL-2, IL-2R, IL-2RG, IL-6, IL-8, 1L-10, IL-17D, IL-18, IFNGR1, JAK2, NLRP3, TNFA, MCP1 and MIP1A (GCSF). (C. Huang, 2020)
IL-1A is a pro-inflammatory cytokine and an important mediator of local and systemic inflammation. Excessive IL-1A release during viral infections can cause lung and tissue inflammation, fever and fibrosis. IL-1 suppression has found to be effective in many inflammatory diseases, including rheumatoid arthritis
IL-1B is a potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, it induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production. It promotes differentiation of the TH17 subset of T-cells.
Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and many other activities crucial to regulation of the immune response. It can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.
The increased expression of IL-2R and IL-6 in serum is expected to predict increased severity of 2019-nCoV pneumonia and a poorer patient prognosis (Chen, L, et al, 2020).
Cytokine receptor common subunit gamma is a common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, it is involved in the stimulation of neutrophil phagocytosis by IL15.
IL-6 is a cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response, plays an essential role in the final differentiation of B-cells into immunoglobulin-secreting cells, and is involved in lymphocyte and monocyte differentiation. IL-6 acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells, and cells of the CNS. It is also required for the generation of TH17 cells.
Increased expression of IL-2R, D-Dimer, and IL-6 in serum was associated with increased severity of 2019-nCoV pneumonia and poorer patient prognosis. (Russell Beth, 2020) (Chen. L, et al)
IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. IL-8 is released from several cell types in response to an inflammatory stimulus.
IL-10 inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF and GM-CSF. IL-10 is produced by activated macrophages and by helper T-cells.
IL-17D induces expression of IL6, CXCL8/IL8, and CSF2/GM-CSF from endothelial cells.
IL-17A is part of the ligand for IL17RA and IL17RC. The heterodimer formed by IL17A and IL17F is the ligand for the heterodimeric complex formed by IL17RA and IL17RC. It is involved in inducing stromal cells to produce proinflammatory and hematopoietic cytokines.
IL-18 augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I (TH1) cells. IL-18 belongs to the IL-1 family.
IFNGR1 associates with IFNGR2 to form the receptor for interferon gamma (IFNG). Ligand binding stimulates activation of the JAK/STAT signaling pathway.
JAK2 is a non-receptor tyrosine kinase involved in various processes, such as cell growth, development, differentiation, and histone modification. The JAK2 pathway mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, JAK2 plays a pivotal role in signal transduction via its association with type I receptors, such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), and thrombopoietin (THPO); or type II receptors, including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation, which may lead to the hypertension observed in some COVID-19 patients. (Guilluy C, 2010)
As the sensor component of the NLRP3 inflammasome, NLRP3 plays a crucial role in innate immunity and inflammation. The SARS-CoV open reading frame 3a (ORF3a) accessory protein activates the NLRP3 inflammasome by promoting TNF receptor-associated factor 3 (TRAF3)-mediated ubiquitination of apoptosis-associated speck-like protein, containing a caspase recruitment domain (ASC). Since the orf3a domain in SARS-COV-2 is approximately 73% similar to SARS-CoV, it is likely to be involved in a similar mechanism (Kam-Leung Siu, 2019).
The TNF family of receptors and cytokines is very large and this family is frequently targeted by drugs. TNFa is a pro-inflammatory cytokine involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. TNFa inhibitors act by suppressing the physiologic response to TNFa.
Inhibition of TNFa can be achieved with a monoclonal antibody, such as Infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi), or with a receptor fusion protein, etanercept (Enbrel). Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. (Russell Beth, 2020)
C-C motif chemokine 2 (MCP1/CCL2) is a chemotactic factor that attracts monocytes and basophils but not neutrophils or eosinophils. CCL2 augments monocyte anti-tumor activity, and has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis, and atherosclerosis.
Granulocyte/macrophage colony-stimulating factors are cytokines that act during hematopoiesis by controlling the production, differentiation, and function of granulocytes,monocytes, and macrophages. GCSF induces granulocytes and belongs to the IL-6 superfamily.