Consequences of an immune response

The immune response is apparently intended to neutralize, detoxify, and help eliminate a foreign material. However, sometimes the immune response can inadvertently cause harm. This will be discussed in various categories in the next section. 

Damage to the implant. The inflammation which is part of the initiation of the immune response is an oxidative response. Materials subject to oxidative attack, such as polyethylenes and polyurethanes, may be degraded. 

Damage to adjacent tissues. Products, particularly from Type II and IV responses, may initiate swelling and other vascular responses at the site. This may resolve with no further harm, or it may cause tissue necrosis and/or loss of tissue mass with loosening or movement of the device. 

Systemic responses. Immune responses of Type I and II generate vasoactive substances which may circulate and cause vascular collapse. This is seen in response to latex materials and drugs which bind to platelets, mast cells, or eosinophils, resulting in an immune response and release of these vasoactive substances. 

There has been a rapid growth in our knowledge of the immune response and how to evaluate and quantitate it. As these techniques are applied to the population in contact with biomaterials, we will learn more about its importance in performance of the material. We will also learn more about how to process the materials to minimize the immune response. However, it is important to remember that the immune response is a protective response and detection of immune responses to products of biomaterials does not necessarily indicate clinical problems. On the other hand, implants are foreign material and will stimulate host responses, some of which may cause harm to the host or implant. 

---

The consequences of an immune response to biological therapeutics are diverse, and often range from a transient appearance of antibodies without any clinical... 

The definition of risk is the probability times the consequences (Figure 20.1). So the probability of an immune response is not synonymous with its risk. A high risk can be associated with a relative high probability, but also with a low probability if the consequences are severe. For example, the probability of an immune response to epoetin is rather low, but one of the consequences, antibody-induced severe anemia, is severe [3], This makes the risk of immunogenicity of epoetins relatively high. 

Halothane reduces splanchnic and hepatic blood flow. Halothane can produce fulminant hepatic necrosis in a small number of patients, a syndrome characterized by fever, anorexia, nausea, and vomiting, developing several days after anesthesia and sometimes accompanied by a rash and peripheral eosinophilia. There is a rapid progression to hepatic failure, with a fatality rate of -50%. This syndrome occurs in about 1 in 10,000 patients receiving halothane and is referred to as halothane hepatitis. Halothane hepatitis may be the result of an immune response to hepatic proteins that become trifluoroacetylated as a consequence of halothane metabolism see Pharmacokinetics, above). 

Cmde enzyme extracts are often unsuitable for therapeutic uses because of their antigenicity, contamination with endotoxins, and rapid inactivation under physiological conditions or in fluids intended for intravenous infusion over several hours. When the enzyme used is a foreign protein, it can eHcit an immune response that alters the clearance rate or induces severe allergic reactions in the host. After an intravenous injection of an enzyme, its activity in plasma decreases with time due to distribution to other fluids and tissues, and as a consequence of proteolysis or excretion. Distribution is related to molecular size, charge, and HpophiHcity surface charges attributable to the availability of free amino, amido, or carboxyl groups may affect the rate of inactivation of some enzymes. 

The TCR is composed of integral membrane protein that recognizes the antigen and as a consequence its activation produces an immune response to eliminate the antigen. This process results in the development of CD4+ or CD8+ cells from the precursor T cells. It involves other cell surface receptors and downstream signal transduction mechanisms. 

The early signals produced during innate immune responses are the main stimuli for the secretion of chemokines. Various chemokines are secreted by a stimulus resulting from viral infection, bacterial products (e.g., LPS) and proinflammatory cytokines including IL-1 and TNF-a. Consequently, some chemokines are proinflammatory in nature and are produced during an immune response to direct leukocytes to the site of injury/infection, whereas others are homeostatic in nature and control the migration of cells during routine tissue maintenance or development. 

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

---