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HLA-B*57:01+ abacavir-naive individuals have specific T cells but no patch test reactivity

2013; Elsevier BV; Volume: 132; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2013.04.013

1097-6825

Benno Schnyder, Jacqueline Adam, Andri Rauch, Maria Christine Thurnheer, Werner J. Pichler,

Asthma and respiratory diseases

Abacavir hypersensitivity (AH) is a potentially severe drug reaction that frequently involves the skin, the liver, and the lung. It is peculiar because of the following features: (a) It is strongly associated with HLA-B*57:01; 47% of HLA-B*57:1 carriers develop AH on exposure. Thus, HLA-B*57:01 has become an established marker for the identification of patients at risk of AH.1Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.PREDICT-1 Study TeamHLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1504) Google Scholar (b) This strong association is not due to a hapten-like reaction to an abacavir-altered peptide but due to noncovalent binding of unmetabolized abacavir to the peptide-binding groove of HLA-B*57:01,2Illing P.T. Vivian J.P. Dudek N.L. Kostenko L. Chen Z. Bharadwaj M. et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.Nature. 2012; 486: 554-558Crossref PubMed Scopus (540) Google Scholar, 3Ostrov D.A. Grant B.J. Pompeu Y.A. Sidney J. Harndahl M. Southwood S. et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.Proc Natl Acad Sci U S A. 2012; 109: 9959-9964Crossref PubMed Scopus (325) Google Scholar, 4Norcross M.A. Luo S. Lu L. Boyne M.T. Gomarteli M. Rennels A.D. et al.Abacavir induces loading of novel self-peptides into HLA-B*57:01: an autoimmune model for HLA-associated drug hypersensitivity.AIDS. 2012; 26: F21-F29Crossref PubMed Scopus (190) Google Scholar, 5Adam J. Eriksson K.K. Schnyder B. Fontana S. Pichler W.J. Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity.Eur J Immunol. 2012; 42: 1706-1716Crossref PubMed Scopus (78) Google Scholar as proposed in the p-i concept.6Adam J. Pichler W.J. Yerly D. Delayed drug hypersensitivity: models of T-cell stimulation.Br J Clin Pharmacol. 2011; 71: 701-707Crossref PubMed Scopus (129) Google Scholar Moreover, this abacavir binding to the HLA-B*57:01 pocket may interfere with peptide loading and cause an alteration of the presented peptide repertoire.2Illing P.T. Vivian J.P. Dudek N.L. Kostenko L. Chen Z. Bharadwaj M. et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.Nature. 2012; 486: 554-558Crossref PubMed Scopus (540) Google Scholar, 3Ostrov D.A. Grant B.J. Pompeu Y.A. Sidney J. Harndahl M. Southwood S. et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.Proc Natl Acad Sci U S A. 2012; 109: 9959-9964Crossref PubMed Scopus (325) Google Scholar, 4Norcross M.A. Luo S. Lu L. Boyne M.T. Gomarteli M. Rennels A.D. et al.Abacavir induces loading of novel self-peptides into HLA-B*57:01: an autoimmune model for HLA-associated drug hypersensitivity.AIDS. 2012; 26: F21-F29Crossref PubMed Scopus (190) Google Scholar The presentation of novel peptides may then elicit either an autoimmune reaction or an alloimmune-like reaction.2Illing P.T. Vivian J.P. Dudek N.L. Kostenko L. Chen Z. Bharadwaj M. et al.Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.Nature. 2012; 486: 554-558Crossref PubMed Scopus (540) Google Scholar, 3Ostrov D.A. Grant B.J. Pompeu Y.A. Sidney J. Harndahl M. Southwood S. et al.Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.Proc Natl Acad Sci U S A. 2012; 109: 9959-9964Crossref PubMed Scopus (325) Google Scholar, 4Norcross M.A. Luo S. Lu L. Boyne M.T. Gomarteli M. Rennels A.D. et al.Abacavir induces loading of novel self-peptides into HLA-B*57:01: an autoimmune model for HLA-associated drug hypersensitivity.AIDS. 2012; 26: F21-F29Crossref PubMed Scopus (190) Google Scholar (c) Abacavir-specific CD8+ T cells are detectable in the circulating blood of B*57:01+ individuals, which were never exposed to abacavir,5Adam J. Eriksson K.K. Schnyder B. Fontana S. Pichler W.J. Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity.Eur J Immunol. 2012; 42: 1706-1716Crossref PubMed Scopus (78) Google Scholar, 7Chessman D. Kostenko L. Lethborg T. Purcell A.W. Williamson N.A. Chen Z. et al.Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity.Immunity. 2008; 28: 822-832Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar and (d) abacavir-specific patch tests in patients with AH show high test accuracy (79%) with an excellent specificity (100%).1Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.PREDICT-1 Study TeamHLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1504) Google Scholar On the basis of these peculiarities and findings, we performed a study (approved by the Ethics Committee of the canton of Bern, Switzerland) in which we asked the following questions:1.Can a pre-existent abacavir reactivity in HLA-B*57:01+ abacavir-naive individuals be detected not only in vitro in the peripheral blood but also in vivo by skin patch testing?2.Does localized abacavir skin exposure in skin patch testing induce reactivity in HLA-B*57:01+ individuals who were not systemically exposed to abacavir? The primary end point was the proportion of positive skin patch test results with abacavir in HLA-B*57:01+ individuals who had never been exposed to abacavir. The secondary end point was the proportion of individuals with positive skin test result in a repeated investigation several months after first patch testing in HLA-B*57:01+ individuals. Nonpregnant female or male volunteers (>18 years) were typed for their HLA-B*57:01 status. The population included the following:•1 HLA-B*57:01+ subject with HIV infection who experienced an immunologically confirmed AH syndrome with generalized maculopapular drug eruption and mild hepatitis on therapy 2002 (positive control).•7 HLA-B*57:01+ HIV-infected subjects without prior abacavir exposition.•6 HLA-B*57:01+ healthy donors without prior abacavir exposition. Ten percent abacavir in petrolatum base was applied to the midback of untreated skin. A second identical abacavir patch panel was applied on skin, where the upper skin layer (keratin) had been removed by scotch tape to facilitate abacavir penetration. All patches were read at 48, 96, and/or 120 hours. Several months later, a further abacavir patch test was performed on the back, but not necessarily the identical site and without scotch tape stripping. Abacavir-specific T cells were generated as described in Adam et al.5Adam J. Eriksson K.K. Schnyder B. Fontana S. Pichler W.J. Yerly D. Avidity determines T-cell reactivity in abacavir hypersensitivity.Eur J Immunol. 2012; 42: 1706-1716Crossref PubMed Scopus (78) Google Scholar On day 14, cells were restimulated in the presence of abacavir for 6 hours and IFN-γ secretion of drug-stimulated CD8+ T cells was analyzed by using flow cytometry (Canto I; Becton-Dickinson, Burlingham, Fla). The only positive patch test result was observed in the patient with a previous AH reaction after systemic exposure to abacavir during treatment. This patient had already tested with positive result 9 years previously and interestingly remained patch test positive. However, none of the ABC-naive persons had a reaction in the first patch test (0/13, 95% CI = 0.0-0.206). In 10 of 13 persons, we could repeat the test after an interval of 6 to 52 months. All repeated test results were negative (0/10, 95% CI = 0.0-0.26). Abacavir-reactive circulating T cells were found in all tested HLA-B*57:01+ individuals (Table I) but in none of the HLA-B*57:01− controls (0/8). Their frequency was similar in the positive control and the HLA-B*57:01 carriers with and without HIV infection.Table IReactivity in patch tests and percentage of circulating, abacavir reactive T cellsSexPrevious exposureHIV infectionPatch IPatch IIInterval patch I-II (mo)Abacavir-reactive T cells (%)MaleYes+Positiven.d.2MaleNo−Negativen.d.0.2MaleNo+NegativeNegative100.32MaleNo+NegativeNegative521.2MaleNo+Negativen.d.n.d.MaleNo−NegativeNegative80.23MaleNo+NegativeNegative470.23MaleNo+NegativeNegative280.25FemaleNo−Negativen.d.n.d.MaleNo+NegativeNegative181.4FemaleNo−NegativeNegative25n.d.MaleNo−NegativeNegative90.9MaleNo+NegativeNegative160.23MaleNo−NegativeNegative491.5n.d., Not determined. Open table in a new tab n.d., Not determined. Our findings can be summarized as follows:1.Patch testing was negative in all investigated abacavir-naive HLA-B*57:01+ individuals in spite of the presence of circulating abacavir-reactive T cells. However, because of the limited sensitivity of patch testing (79%) and the small sample size of the study, pre-existent skin reactivity cannot be excluded (0/13, 95% CI = 0%-20.6%). It is possible that reactive skin T cells pre-exist in those who develop a very early reaction within a few days on abacavir exposure. Nevertheless, the result provides evidence that pre-existent skin reactivity, if this indeed occurs at all, is the exception rather than the rule. Patch testing is consequently unable to discriminate between HLA-B*57:01+ individuals who would develop a "true" AH on systemic exposure and individuals who would tolerate abacavir.2.Repeated patch testing in ABC-naive HLA-B*57:01+ individuals showed no positive reaction (0/10, 95% CI = 0.0-0.26). Thus, local cutaneous abacavir exposure seems not to be a strong stimulus for the induction of skin reactivity ("sensitization") in HLA-B*57:01+ individuals. However, as we did not always apply the second abacavir to exactly the same skin area as the first, we cannot exclude that patch testing induces a local accumulation of memory T cells.3.Patch test reactivity in patients with previous abacavir skin symptoms can persist for more than 9 years. How can one explain the finding of a consistent abacavir-specific reactivity of circulating T cells in abacavir-naive, B*57:01+ individuals while the same individuals show no skin reactivity after local abacavir application by patch testing? Patch test reactivity is found in most of the HLA-B*57:01+ patients with previous AH1Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.PREDICT-1 Study TeamHLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1504) Google Scholar and was also found in our positive control. Thus, a prior generalized AH seems to be a precondition for skin reactivity. As recently shown in the mouse model,8Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (641) Google Scholar the accumulation of long-lasting memory resident T cells in the skin requires a prior generalized inflammatory reaction, for example, from vaccinia virus. Without such prior systemic immune reaction, the T cell would not home to the skin and no accumulation of memory resident T cells would occur. We assume that systemic exposure to abacavir is a strong stimulus similar to that of a virus infection, which is able to cause a systemic reaction and accumulation of memory resident T cells in the skin persisting for many years. Without this systemic reaction, abacavir-reactive T cells would not home to the skin and patch test results would remain negative, although reactive T cells would be available. This explanation would also fit with our observation that abacavir patch testing does not seem to sensitize. Because abacavir stimulates via the p-i concept, the local exposure achieved by patch testing is unlikely to be sufficient to activate T cells and recruit them to the skin. In conclusion, while all HLA-B*57:01+ individuals have abacavir-reactive T cells in the circulation, skin testing in abacavir-naive individuals is negative and does not appear to sensitize. Only patients with prior AH still have abacavir-reactive T cells in the skin years after the hypersensitivity reaction. The data are compatible with the concept of memory resident T cells homing to the skin during a prior systemic reaction like an AH. Further work is needed to support this hypothesis and to address the mechanism and details of abacavir-reactive T cell stimulation and its effect on the skin. We thank all patients and volunteers for participating in this study. We also thank the study nurses of the Department of Infectious Diseases, Inselspital, Susanne Z'Graggen, Cornelia Krismer, and Christine Brülisauer, and the Swiss HIV-cohort study (SHCS).