Autoimmunity predicting

Anti-TPOAb Less than 1 00 units/mL Present in autoimmune hypothyroidism predicts more rapid progression from subclinical to overt hypothyroidism... 

Kuper, C.F. et al., Predictive testing for pathogenic autoimmunity the morphological approach, Toxicol. Lett., 112-113 433, 2000b. 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Genetically predisposed animals or induced animal models may also be used to study and predict chemical-induced autoimmunity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis (AA), experimental allergic encephalomyelitis (EAE) and experimental uveitis in the Lewis strain rat. Examples of spontaneous models... 

The rationale behind using autoimmune-prone animal strains to study and predict autoimmunogenic potential of chemicals is that exacerbation of disease is one of the possibilities by which chemicals may elicit autoimmune phenomena [5, 61]. 

Irreversible inhibition of CYPs is particularly worrisome as its consequences cannot be predicted easily or quantified from in vitro data the in vivo effect of an irreversible inhibitor is usually greater than that predicted based on affinity alone. Moreover, irreversible inhibition is generally the consequence of the production of reactive metabolites (electrophiles), which can also bind covalently to endogenous proteins and, in rare cases, trigger serious autoimmune reactions [4]. 

An autoimmune response is rarely detected during preclinical drug development because of the lack of good predictive animal models for the human immune system. Owing to their low incidence and idiosyncratic nature, autoimmune diseases quite often appear as a serious issue only after product launch [2,22]. 

Because of the idiosyncratic nature of chemical induced autoimmunity (including drug allergy) it is impossible to predict this phenomenon in routine toxicity studies... 

Outcomes of in vitro methods or simple in vivo methods such as the PLNA, only indicate whether a compound can sensitize the immune system. They do not predict whether a compound can induce an autoimmune disease. For that disease models are warranted. However, most disease models, as mentioned, will often require predisposed animal strains such as systemic lupus erythematosus (SLE)-prone mice [81, 82]. Often models using autoimmune-prone mice or rats (including the BN rat) are considered too sensitive and are for that reason undesired by various stakeholders (i.e., pharmaceutical industries, regulatory agencies). 

In patients with chronic hepatic B or C the respective prevalences of pancreatic autoantibodies increased from 2% and 3% at baseline to 5% and 7% after interferon (544). In all, 31 published cases of type 1 diabetes mellitus attributed to interferon alfa treatment were detailed, mostly in patients with hepatitis C. Irreversible diabetes required permanent insulin treatment in all but eight cases. At least one marker of pancreatic autoimmunity was positive in nine of 18 patients before treatment, and in 23 of 30 patients at the onset of diabetes. In accordance with these results and the likelihood of a genetic predisposition, the authors recommended screening for islet cell and glutamic acid decarboxylase autoantibodies before and during interferon alfa treatment. However, owing to the low number of reported cases and the paucity of studies that have examined the relation between pancreatic autoimmunity and the occurrence of diabetes, further research on the predictive potential of such a systematic investigation is warranted. 

In 106 patients (76 women) with multiple sclerosis who received interferon beta-la or beta-lb for up to 84 (median 42) months, there was baseline thyroid autoimmunity in 8.5% and hypothyroidism in 2.8% (562). Thyroid dysfunction (80% hypothyroidism, 92% subclinical, 56% transient) developed in 24% (68% with autoimmunity) and autoimmunity in 23% (46% with dysfunction), without a significant difference between the two cytokines 68% of the cases of dysfunction occurred within the first year. Thyroid dysfunction was generally subclinical and was transient in over half of cases. Autoimmunity was the only predictive factor for the development of dysfunction (relative risk = 8.9), but sustained disease was also significantly associated with male sex. 

Bridging Mice to Men Using HLA Transgenic Mice to Enhance the Future Prediction and Prevention of Autoimmune Type 1 Diabetes in Humans... 

Alopecia Areata Alopecia areata is a relatively common autoimmune skin disease that affects humans, mice, rats, horses, dogs, cattle, and even a feather form in chickens (26). Although the disease occurs spontaneously, mice have a low frequency of disease. Full thickness skin grafts provided a reproducible and predictable model (53). This mouse has been used effectively to test drugs known to work on humans with alopecia areata by all methods discussed in this chapter (27). 

Wirtz PW, Willcox N, van der Slik AR, Lang B, Maddison P, Koeleman BP, et al. HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome. J Neuroimmunol 2005 159(l-2) 230-237. 

Our currently poor understanding of the mechanisms leading to autoimmunity and autoimmune diseases following drug therapy is a major hurdle. To date, no animal model or assay can reliably predict the potential, of biopharmaceuticals or pharmaceuticals, for inducing autoimmunity reactions in human subjects. 

The prediction of peptides which bind to major histocompatibility complex (MHC) molecules is important for identifying autoimmune and CTL epitopes and for peptide vaccine design because the MHC-binding is a necessary condition for the peptide to be a T-cell epitope. Although MHC-binding peptides exhibit certain common sequence motifs, they are neither necessary nor sufficient for binding. Many binding peptides do... 

L. Cascioia-Rosen, F. Andrade, D. Ula-NET, W. B. Wong, A. Rosen, Cleavage by granzyme B is strongly predictive of autoantigen status implications for initiation of autoimmunity. J. Exp. Med. 

---