HLA TYPING AS DIAGNOSTIC TOOL

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HUMAN LEUKOCYTE ANTIGEN TYPING AS DIAGNOSTIC TOOL IN DRUG-INDUCED HYPERSENSITIVITY:

HUMAN LEUKOCYTE ANTIGEN TYPING AS DIAGNOSTIC TOOL IN DRUG-INDUCED HYPERSENSITIVITY OLUDARE OLABISI E. Edited by Omotoso Kayode

TABLE OF CONTENT:

TABLE OF CONTENT INTRODUCTION HUMAN LEUCOCYTE ANTIGEN (HLA) ALLELES DIAGNOSIS OF DRUG-INDUCED HYPERSENSITIVITY HLA AND DRUG-INDUCED HYPERSENSITIVITY CLINICAL UTILITY OF HLA TESTS CONCLUSION

INTRODUCTION:

INTRODUCTION Adverse drug reactions (ADRs) are one of the leading causes of morbidity and mortality in healthcare. (Johnson and Bootman , 1995) In addition to increasing the burden on the healthcare system, ADRs limit the use of key drug therapies. 2 major categories of ADRs: The predictable (Type A) ADR, The idiosyncratic (Type B) ADR also known as drug hypersensitivities. ( Pichler , 2003)

INTRO CONT’D:

INTRO CONT’D Drug hypersensitivities constitute approximately 13% of ADRs and are typically more severe in nature than the predictable drug reactions. ( Hunziker et al, 2002; Naisbitt et al, 2004) Therefore, understanding the mechanisms behind these reactions is highly desirable for both prognosis and prevention.

Symptoms of Drug-Induced Hypersensitivity (Adapted from European Network of Drug Allergy Questionnaire):

Symptoms of Drug-Induced Hypersensitivity (Adapted from European Network of Drug Allergy Questionnaire)

INTRO CONT’D:

INTRO CONT’D Over the last few decades, attempts to understand the etiology of idiosyncratic drug reactions has led to the discovery of associations between various reactions and particular alleles of the human leukocyte antigen (HLA). ( Mandvi et al, 2010)

HUMAN LEUKOCYTE ANTIGEN ALLELES:

HUMAN LEUKOCYTE ANTIGEN ALLELES The major histocompatibility complex ( MHC) located on the short arm of chromosome 6 has an essential role in the innate and adaptive immune system. It contains a large number of highly polymorphic genes characterised by high linkage disequilibrium. Because of the importance of the MHC region in immunity, and in the aetiology of many autoimmune diseases , great effort has been made to sequence, analyse and annotate this region. (Beck et al, 1999; Mungall et al, 2003).

HLA CONT’D:

HLA CONT’D The MHC region includes genes in the human leukocyte antigen (HLA) Class I, II and III. HLA class I contains HLA-A, HLA-B and HLA-C Class II contains HLA-DR, HLA-DP and HLA-DQ Class III contains TNF- α gene, lymphotoxin alpha (LTA), heat shock proteins and many other non-immune related genes. (Marsh et al, 2010)

HLA CONT’D:

HLA CONT’D MHC molecules are polymorphic cell surface glycoproteins that present peptide antigens to T cells. This antigen presentation is crucial for the regulation of protective immune responses against pathogens and for the maintenance of self-tolerance. HLA-B is the most polymorphic gene in the human genome containing more than 1,600 alleles. ( Alfirevic and Pirmohamed , 2011)

HLA CONT’D:

HLA CONT’D HLA alleles confer protection against infectious and immune diseases e.g. Caucasians possessing HLA-B*5701 and African Americans with HLA-B*5703 are resistant to HIV. ( Migueles et al, 2000; Pelak et al, 2010) However, alleles strongly associated with HIV-1 disease progression showed no effect in HIV-2 disease. ( Yindom et al, 2010)

HLA CONT’D:

HLA CONT’D HLA alleles are also associated with an increased risk of other diseases e.g. Autoimmune diseases Drug-induced hypersensitivity. ( Alfirevic and Pirmohamed , 2011)

DIAGNOSIS OF DRUG-INDUCED HYPERSENSITIVITY (DIH):

DIAGNOSIS OF DRUG-INDUCED HYPERSENSITIVITY (DIH) Hypersensitivity reactions can be induced by a large number of drugs e.g. NSAIDs, abacavir etc. Causality is difficult to establish based on time-event relationship. Clinical manifestation ranges from mild skin reactions to life threatening systemic symptoms. ( Alfirevic and Pirmohamed , 2011)

DIAGNOSIS CONT’D:

DIAGNOSIS CONT’D Given the heterogeneity of the clinical symptoms, it is difficult to diagnose drug-induced hypersensitivity (DIH). ( Roujean , 2005) Both in vivo and in vitro tests are available to confirm the diagnosis of DIH e.g. Skin patch testing. ( Elzagallaai et al, 2009) Lymphocyte transformation test (LTT). ( Schellekens and Eijsvoogel , 1968)) Lymphocyte toxicity assay (LTA). (Shear and Spielberg, 1968)

DIAGNOSIS CONT’D:

DIAGNOSIS CONT’D The skin patch test is an in vivo immune function test used in measuring the presence of activated T cells. The LTT and LTA are in vitro tests using peripheral blood mononuclear cells (PBMCs) as target cells. Although they are well deployed in the laboratory for research purposes, their clinical use are rather very low. ( Alfirevic and Pirmohamed , 2011)

HUMAN LEUKOCYTE ANTIGEN AND DRUG-INDUCED HYPERSENSITIVITY:

HUMAN LEUKOCYTE ANTIGEN AND DRUG-INDUCED HYPERSENSITIVITY Different HLA alleles represent important risk factors for hypersensitivity induced by several drugs in patients of variable genetic ancestry. HLA alleles have been identified as risk factors for DIH since the 1980s. ( Alfirevic and Pirmohamed , 2011)

PowerPoint Presentation:

DRUG REACTIONS HLA-allele POPULATION REFRENCE Carbamazepine SJS/TEN B*1502 Han Chinese, Thai, Malay, Indian Man, 2007; Tasseneeyakul , 2010; Ding, 2010. Allopurinol SJS/TEN B*5801 Han Chinese, Thai, Japanese, Malay Hung, 2005; Kaniwa , 2008; Ding, 2010 Oxicam SJS/TEN A2, B12 Caucasians Roujeau , 1987 Abacavir DRESS B*5701 Caucasians Martins, 2004; Mallal , 2008 Aminopenicillins DRESS A2, Drw52 Caucasians Romano, 1998 Aspirin DRESS DRB1*1302, DQB1*0690 Kim, 2005; Palikhe , 2008 Lamotrigine DRESS B*5801 Caucasians Kazeem , 2009 HLA ALLELE ASSOCIATION WITH DIH IN DIFFERENT POPULATIONS.

PowerPoint Presentation:

DRUG REACTIONS HLA-allele POPULATION REFRENCE Co- trimoxazole Fixed drug eruption A30, B13, Cw6 Caucasians-Turkish Ozkaya-Bayazit , 2001 NSAIDs Nephritis DR Japanese Joh , 1990 Flucloxacillin Liver toxicity B*5701 Caucasians Daly, 2009 Lumiracoxib Liver toxicity DRB1*1501, DQA1*0102 Singer, 2010 Co- amoxiclav Liver toxicity DRB1*1501 Hautekeete , 1999; O’Donohue , 2000 Diclofenac Liver toxicity DRB1*13 Daly, 2009

CLINICAL UTILITY OF HLA TESTS:

CLINICAL UTILITY OF HLA TESTS The predictive value of HLA-B*5701 testing for preventing abacavir hypersensitivity has been confirmed in a prospective clinical trial and is already being implemented in many high- to medium income countries . ( Alfirevic and Pirmohamed , 2011) It has also been found to be cost-effectiveness. (Hughes et al, 2004)

CLINICAL UTILITY CONT’D:

CLINICAL UTILITY CONT’D Chen et al (2009) conducted a prospective clinical trial of nearly 5,000 patients who were prescribed carbamazepine to assess the cost- effectivness of HLA-B*1502 pre-treatment testing. HLA-B*1502 genotyping can reduce the occurrence of SJS/TEN and the healthcare system could save millions if CBZ was prescribed only to those individuals who are B*1502 negative.

CONCLUSION:

CONCLUSION Robust genetic markers to predict susceptibility to drug-induced hypersensitivity are still lacking. However, the HLA allelic associations may be clinically beneficial through the use of tests of exclusion and diagnostic aids.

THANK YOU:

THANK YOU

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