By Disease

The discovery of molecules such as PD-1 on T cells has paved the way for tapping the immune system in combating cancer. The advancement of technologies and understanding of the interplay of various immune cells exposes the role of new immune cell mechanisms in cancer. The research around the tumor microenvironment (TME) has led to the discoveries of immune suppressive mechanisms such as Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and Regulatory T cells (Tregs). Further studies have highlighted the role of the tumor stroma and extracellular matrix (ECM) towards the resistance of tumors to immunotherapy. Immuno-oncology represents a major aspect of our business and we have invested heavily in the development of novel cell lines and assay platforms to help our partners screen for the right drug candidates early in the development process.

Relevant assays for this disease:

Multiple sclerosis (MS) is a neurological disorder characterized by inflammation and destruction of the myelin protective sheath of axons within the brain and spinal cord (1). The etiology of MS is complex and likely results from a combination of genetic predisposition coupled with environmental insult (e.g. infection). However, the pathogenesis and progression of MS is driven by unintended attack by cells of our own immune system. Animal models of MS together with analysis of peripheral blood and CNS lesions in MS patients have demonstrated CD4⁺ T “helper” cells are the primary pathogenic cells driving disease progression (1-3). Despite some differences between mouse and human studies, it is believed that a special subset of Th17 CD4⁺ T cells that infiltrate the CNS and secrete both IFNg and IL-17 are the main drivers of disease (4-6).

Relevant assays for this disease

Rheumatoid arthritis (RA) is an chronic inflammatory disease characterized by immunological destruction of synovial membranes that drives joint pain (7). Development of disease is typically associated with CD4⁺ Th1 cell although CD4⁺ Th17 cells and production of the cytokines IL17A/F, IL21, IL22, TNFa are all important in disease progression. Furthermore, diminished function and numerical accumulation of CD4⁺ Foxp3⁺ regulatory T cells (Tregs) have been observed in disease tissue (8-10). B cells that produce autoantibodies against synovium proteins are also important drivers of disease pathogenesis and likely contribute to disease chronicity(11). These B cells have even been shown to form lymphoid structures within disease tissue to promote interaction with local T cells and localized generation of antibody-secreting plasmablasts (11).

Relevant assays for the disease:

SLE is an autoimmune disorder that effects multiple organ systems. A hallmark characteristic of SLE is the B cell production of autoantibodies against cell nucleus associated proteins, double-stranded DNA, etc (12). This is driven by unleashed activation CD4⁺ Th2 cells that produce cytokines such as IL-4 that promote B cell activation and antibody class switching (12). Additionally, an imbalance of Th17 to Treg cells is also associated with the progression of disease (13). It is believed that T cell activation is likely triggered by excessive production of type I interferons in response to environmental insults such as infection (14).

Relevant assays for the disease:

Psoriasis is a chronic skin disease generally characterized by hyperproliferative skin cells (keratinocytes) that form thick, scaly patches known as plaques (15, 16). Infiltration of white blood cells such as T cells within the dermis layer of psoriatic lesions are considered a main driver of inflammation and a hallmark of the disease (17, 18). Studies from psoriasis patients suggest increased expression melanocyte and keratinocyte proteins by psoriasis patients likely serves as a target for autoimmune inflammation (19, 20). It is generally believed that CD4⁺ Th1, Th17 and CD8⁺ Tc17 cells that secrete IFNg and IL-17a in response to these self-antigens are the main pathogenic drivers in the progression of psoriasis (16, 21-25).

Relevant assays for this disease:

Scleroderma (systemic sclerosis) is an autoimmune disorder characterized by overactive collagen deposition (fibrosis) in the skin and other systemic (e.g. heart, lung, esophagus and kidneys) eventually leading to organ failure (26). Scleroderma pathogenesis is driven by the production of anti-nuclear antibodies (ANAs) that target nuclear proteins (e.g. topoisomerase I, DNA) (27, 28). Additionally, agonist autoantibodies that can trigger aberrant activation of  cellular signaling cascades such as the platelet-derived growth factor receptor (PDGFR) have been thought to drive pathogenesis (26, 27). Excessive B cell activation and secretion of IL-6 and TGF-b both systemically and in the skin have also observed in scleroderma patients when compared to healthy controls (29-32). T cell infiltration into patient skin has also been observed (33-35). Specifically, CD4⁺ Th2 cells secreting IL-4 and IL-13 are readily found in circulation of scleroderma patients and likely amplify B cell activation and downstream fibrosis (36). Several studies have also shown decreased numbers and functional defects in CD4⁺ regulatory T cells (Tregs) both peripherally and within diseased skin (36, 37).

Relevant assays for this disease:

T2D is a metabolic disorder associated with pancreatic beta cell dysfunction and insulin resistance. Development of T2D commonly parallels obesity or adiposity which is known to trigger systemic inflammation and drive disease pathogenesis. In turn, obesity-associated inflammation can contribute to activation of tissue-resident T and B cells or innate cells like macrophages and dendritic cells (47, 48). Increased ratio of CD8⁺ T cells compared with CD4⁺ T cells within adipose tissue has also been demonstrated in obese individuals likely due to reciprocal decreased in regulatory T cells. Production of IFNg by CD8⁺ T cells and Th1 CD4⁺ T cells also likely drives infiltration from innate cells including M1 macrophages that produce nitric oxide and TNFa can directly dampen insulin production (48).

Relevant assays for this disease:

UC is a disorder associated with abnormal inflammation restricted to the rectum/colon that eventually leads to the formation of ulcers within the inner lining of the intestine. Although the cause of UC is generally unknown, it is believed intestinal infection can trigger dysregulation of inflammation within the localized innate cells such as dendritic cells (56). This disrupts the normal antigen presentation and tolerance process. In turn, production of inflammatory cytokines (e.g. IL-1, IL-6, IL-33) drive disease progression by recruiting CD4⁺ Th1 and Th17 T cells as well as NK cells producing IFNg, IL-17, IL-22 that are critical for UC pathogenesis. In turn dampened recruitment, activation and suppressive potency of Tregs also contributes to disruption of normal tolerance within the gut to commensal microbes leading to detrimental attack of these beneficial species.

Relevant assays for this disease:

Fibrosis generally describes the excessive deposition of collagen and other extracellular matrix components within a variety of different organs. One contributing factor is likely unregulated response to repairing damage from environmental insults (e.g. physical trauma, infection). To this end, imbalance of CD4⁺ T cells toward Th2 or Th17 instead of Th1 cells exacerbates secretion of cytokines that promote a pro-fibrotic milieu (50). Furthermore, both defective suppressive potency of CD4⁺ Tregs or their conversion to pathogenic Th17 cells has been considered important to disease progression (50-52). Within some tissue-specific fibrosis disorders, autoantibody production or secretion of inflammatory cytokines by activated B cell also contribute to increased fibrosis (53).

Relevant assays for this disease: