What is "Self-Tolerance"?
Self-tolerance is the ability of the immune system to recognize self-produced antigens as a non-threat while appropriately mounting a response to foreign substances. This balance of immunological defense and self-tolerance is critical to normal physiological function and overall health. Self-tolerance mechanisms play roles in cancer, auto-immune diseases, colonization by commensal bacteria, and pregnancy.
As lymphocytes develop, the receptor sequences are generated completely at random. This indiscriminate approach results in such a diverse variety of receptors that nearly any antigen the immune system encounters may be recognized. However, this amazingly broad repertoire inevitably contains receptors that can recognize endogenous antigens, self-made molecules which the immune system should not attack. In order to reduce the scope of lymphocytes recognition and subsequent attack of foreign antigens, the immune system employs a series of checks known generally as "self-tolerance". Self-tolerance regulation of immune effector cells can be divided into two mechanisms termed "central tolerance" and "peripheral tolerance," depending on where they take place. Central tolerance occurs in the organ of maturation for the respective lymphocyte, the thymus for T-Cells and bone marrow for B-Cells. Peripheral tolerance occurs outside the organ of maturation, at the site of antigen recognition where the T-Cells and B-Cells would ultimately begin to elicit an immune response. Specifically, this can occur in the circulation, lymph node, lymph organ, or other tissues. Read More »
Self-Tolerance Disease Involvement
Self-tolerance is a complicated system of safeguards that may be corrupted at any stage. Autoimmune disorders result from any number of missteps in the self-tolerance system. Some pathogenic states in which autoimmunity has been implicated include: idiotype cross-reactivity, epitope drift, and aberrant BCR-mediated feedback. Self-tolerance errors result in autoimmune disorders such as celiac disease, type-1 diabetes, inflammatory bowel disease (IBD), multiple sclerosis to name a few. Self-tolerance mechanisms also provide barriers to therapeutic interventions. Tissue engraftment after transplant procedures prove difficult as the immune system correctly recognizes allopatric antigens from the donor tissue as foreign. Manipulation of the immune system towards tolerance of transplanted tissue expressing non-self-antigens would be diminish graft rejection. Conversely, immune response to cancer cells is blunted due to appropriate self-tolerance response as cancer cells express self-antigen. In this case, effective immunotherapy against cancer requires breaking of the self-tolerance mechanisms.
Research Implications of Self-Antigen and Self-Tolerance
A major challenge researchers face when generating antibodies against high homology antigens is overcoming self-tolerance. Generating sufficient response to antigen requires the self-tolerance mechanisms outlined here to be precisely overcome. While this is a daunting task, GenScript has developed proprietary technology to do just that. Our ImmunoPlus™ Technology utilizes key immunomodulators to circumvent self-tolerance mechanisms and allow B-Cells to generate high affinity antibodies.
Surrogate antibodies are just one instance where antibodies to self-antigens with high homology are needed. Surrogate antibodies can be a means of testing eventual safety and efficacy of human therapeutic antibodies in mouse models. Targeting the correlate antigen in a mouse with a mouse generated antibody can provide some understanding of a humanized antibody in human system can be gained. Specifically, the degree of toxicity and efficacy can be surmised and extrapolated to a human model. The following case study exemplifies the differences between traditional immunization and ImmunoPlus™ supplemented regimens. The antigen target maintains a 96% homology between the human and mouse sequences. While this resulted in poor titres from regular immunizations, self-tolerance manipulation allows for an approximate 10-100 fold increase in the immune response.
Self-Tolerance Related Services
GenScript has over 12 years of experience developing customized antibodies against difficult targets. Our ImmunoPlus™ technology is available through our Custom mAb and Custom pAb services. You can even utilize ImmunoPlus™ in our Semi-Custom mAb Production Service which simplifies custom mAb protocols to 3 easy steps. Some other related services include:
- DNA Immunizations, our specialty. Circumvents in vitro protein antigen production and deals with difficult targets.
- High Throughput Gene to Antibody up to 1mg of recombinant antibodies in as little as 3 weeks.
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