Allergic reactions to drugs are a significant problem in clinical practice and can lead to patient morbidity and mortality, increased costs of treatment and limited future treatment options. Such reactions also add to the cost and uncertainty of drug development. The Drug Hypersensitivity research group at IIID, led by Prof Elizabeth Phillips is focused on investigating the immunological mechanisms driving allergic reactions to drugs. Abacavir (ABC) hypersensitivity syndrome and its association with the carriage of HLA-B*57:01 has been one of our research since our group reported this in 2002. Since the discovery of this association we have championed the translation of HLA-B*57:01 screening to prevent ABC hypersensitivity. We have also made progress in defining the basis of the predisposition of HLA-B*57:01 carriers to ABC hypersensitivity and more broadly the immunopathogenesis drug hypersensitivity reactions. Together with our collaborators we have published how ABC non-covalently binds to HLA-B*57:01 and consequently alters the peptide binding specificity (altered peptide repertoire hypothesis). It is anticipated that this model may form the basis for many T-cell mediated severe drug reactions. Further investigation of the immune mechanisms driving ABC hypersensitivity and other hypersensitivity syndromes related to drugs such as carbamazepine, nevirapine, allopurinol and drug commonly used in clinical practice such as penicillin are the focus of our current research.
Pharmacogenomics and mechanistic basis of drug hypersensitivity
We propose that an altered-peptide heterologous immunity model, analogous to that which explains organ transplant rejection, together with the altered peptide repertoire model, accounts for the clinical and immunopathogenetic features of HLA-restricted drug hypersensitivity such as: ABC hypersensitivity syndrome and carbamazepine (CBZ) associated Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). In the setting of organ transplantation memory CD8+ T-cell responses to prevalent Herpes-virus infections may cross recognize allo-MHC-I-peptide to mediate rejection. We therefore postulate that in the case of HLA class I restricted drug hypersensitivity reactions, similar virus specific memory CD8+ T-cell responses may cross recognize MHC-I-drug-peptide complexes. In addition to testing a heterologous immunity model for ABC hypersensitivity, we propose to examine whether the altered peptide and heterologous immunity models can be generalised to explain the basis of CBZ associated SJS/TEN, another MHC-I associated, CD8+ T-cell mediated reactions. (This work is funded by the NHMRC.)
HLA-associated drug hypersensitivities: functional basis of clinical phenotypes and applications to safer drug development
It is known that some drugs non-covalently bind HLA risk alleles in a site-specific way and thereby alter the peptide binding specificity (altered peptide repertoire hypothesis). Convincing data to support the altered peptide model has been published for phenotypically distinct severe adverse drug reactions such as abacavir hypersensitivity and carbamazepine associated Stevens-Johnson syndrome/toxic epidermal necrolysis, and therefore it is anticipated that this model may form the basis for many T-cell mediated severe drug reactions. In addition recent associations have been elucidated between severe cutaneous phenotype reactions to nevirapine and HLA-B*35:01/05 and nevirapine hepatitis phenotype reactions and HLA-DRB1*01:01/02. A comprehensive in silico assessment of interactions with all FDA approved small molecule and all HLA B alleles has been conducted using molecular docking and modelling prediction software, and this has identified structural analogues of abacavir and nevirapine that do not interact with HLA-B-57:01 and HLA-B/HLA-DRB1*01, respectively. The abacavir and nevirapine case studies will be used to illustrate the specificity of HLA-drug interaction and how pre-clinical screening of these interactions can lead to the development of safer drug development. We will undertake high throughput virtual screening and utilize structural, biochemical and functional approaches to develop pre-clinical screening strategies of new drugs for possible HLA-interaction. Applicability of this approach will be demonstrated in FDA approved small molecule drugs successfully translated to clinic versus well-known examples of drugs associated with drug hypersensitivity syndromes or those that have failed in clinical trials. (This work is funded by the ACH2).