Autoimmunity

Immunotherapeutic strategies are being utilized to harness the power of the immune system to recognize and destroy cancerous cells.  However key challenges remain.  While immune checkpoint inhibitor therapy can provide a more effective therapeutic option for many different advanced stage cancers; it is only effective in 30-40% of patients and nonspecific immunologic activation can lead to immune-related adverse events, including muscle weakness, joint pain, inflammatory arthritis, and myositis.  In addition, immunotherapeutic strategies such as adoptive cell therapy and chimeric antigen receptors can be extremely expensive. Therefore it is imperative to develop tools that can be used to help stratify patients that would best benefit for specific types of immunotherapy, utilize model systems to study the tumor microenvironment in order to develop better combinatorial approaches, and support platforms that can aid in the identification of prognostic and predictive biomarkers.

Scleroderma (or systemic sclerosis) is an autoimmune disorder characterized by fibrosis (overactive collagen deposition) both in the skin and other systemic organs including the heart, lung, esophagus and kidneys. Immune cells such as macrophages (M2 macrophages), Th1 and Th17 cells are recruited during inflammation whereas the Th2 cells have been shown to be involved in disease pathogenesis. For scleroderma patients, the majority of therapeutic success involves treating patients with B cell and T cell depleting antibodies or through autologous hematopoietic stem cell transplantation (following non-myeloablation of immune cells).

IMMUNE 3D^® provides an effective platform to study the role of immune cells such as Tregs and other immunosuppressive populations that could serve as potential targets for novel therapies or biomarkers of disease.

Psoriasis is a chronic disease that afflicts 2-3% of the world’s population. The most common form, plaque psoriasis, is characterized by hyperproliferative skin cells (keratinocytes) that result in thick, scaly patches of skin known as plaques. More recent studies have demonstrated T cells are the predominant leukocytes within psoriatic lesions and the main driver of inflammation. To this end, treatment with broad immunosuppressants (e.g. cyclosporine) or drugs targeting T cell activation (e.g. CTLA-4 Ig) have proven effective [albeit non-specific] therapies. A pathogenic role for IL-17 producing T cells (Th17 cell) has led to development of new therapeutic strategies that directly target their effector cytokines (IL-17A) or the cytokine IL-23 that promotes the recruitment and development of Th17 cells in diseased tissue. These therapies have led to remarkable remission of symptoms in some patients while others seem to still retain resistance to treatment, likely resulting from the contribution of other IL-17 isoforms (e.g. IL-17F), TNFα, IL-22.

IMMUNE 3D^® presents a unique system to cost effectively elucidate the role for T cells and other immune cells such as macrophages and neutrophils in the pathogenesis of psoriasis.

Fibrosis is characterized by excessive deposition of collagen and other extracellular matrix components in a variety of different organs. This typically results from hyperactivity of fibroblasts within or myofibroblasts within a given tissue. While fibrosis contributes to many different diseases (e.g. non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, psoriasis, scleroderma) it likely is a result of disrupted regulation of a normal repair process in response to exogenous insults (e.g. physical trauma, infection). While in some capacity this could reflect intrinsic defects in these tissue cells (keratinocytes, fibroblasts) it is also likely exacerbated by increased and unperturbed inflammation within the tissue environment. Th1 predominant response is protective while imbalance of Th2 and Th17 cells leads to a pro-fibrotic milieu.  However, the direct role of IL-17 in promoting or dampening fibrosis is controversial considering its expression is decreased in certain fibrotic disease patients.

IMMUNE 3D^® aims to elucidate the role of lymphocyte migration and infiltration in regulating the fibrotic diseases.