Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

Future Perspective

Although, in vitro studies have the potential to isolate the role of associated HLA in drug hypersensitivities, both confirming causative roles and advancing efforts to prevent these reactions, as mentioned earlier, the confounding factor remains that despite 100% prevalence in hypersensitivity episodes, a relevant allele may also be present in drug-tolerant individuals. This is a clear indication that a specific set of conditions, not fulfilled by the HLA-association alone, must be met for disease manifestation, and it may eventuate that these conditions need to be determined and replicated for in vitro studies to progress.

Further genetic polymorphisms such as those in genes involved in cytokine production[71–74,111] and drug metabolism[78,79] have been implicated in the manifestation of hypersensitivity and may need to be considered. Furthermore, it is conceivable that polymorphisms, or tissue-specific gene expression, may result in the presence or absence of a peptide component of the immunogenic complex in different individuals and different cell types.

Alternatively, factors associated with the underlying disease status of an individual, such as CD4+ and CD8+ T-cell counts in nevirapine hypersensitivities and AHS, respectively,[31,86] and renal function in allopurinol hypersensitivities,[112] have suggested roles in hypersensitivity and may be key to generating the conditions necessary for drug-induced T-cell activation. Further layers of complexity may also be generated by environmental factors, such as diet, which can affect drug activity.[113]

Without understanding of these other parameters, study of the mechanistic roles of HLA alleles may present an insurmountable challenge. That in vitro studies of AHS have progressed so far without knowledge of the conditions additional to HLA-B*5701 necessary for hypersensitivity may be considered extreme good luck.

In our view there are two important directions that are crucial for the management of HLA-associated drug hypersensitivities. The first, and most obvious, is assessing the benefits and practicality of prescreening for HLA to preclude potential hypersensitivity sufferers, as has been performed with AHS.[33] The utility of pharmacogenetic testing is dependent on several factors including specificity, sensitivity, reproducibility, precision, cost–effectiveness and ease of testing,[103] as such all of these need to considered for each association. This angle has the most immediate translation into the field of personalized medicine. However the second, less obvious and potentially more informative angle, is to investigate the underlying immunology behind these reactions. Not only might such understanding help tailor new, alternative drug therapies for hypersensitive patients, but it may also give us an insight into the mechanisms behind HLA-associated autoimmune diseases such as ankylosing spondylitis, Behçet's disease and birdshot retinopathy, which may follow a similar mechanism, although the causative stimuli in these autoimmune reactions remain unknown.[114–116]

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