Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Phillips, Elizabeth; Mallal, S.

doi:10.1172/jci121525

Cited by 14 publications

(11 citation statements)

References 16 publications

(21 reference statements)

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“…Our results are consistent with the earlier reports 14,18,19 that CD8 and not CD4 T cells are responsible for abacavir‐induced immune response in HLA‐B*57:01 pos ABH pos individuals. It has also been hypothesized that CD4 T cells contribute to the tolerance of abacavir in HLA‐B*5701 patients, leading to the high number of false positives through HLA screening 22 . On the contrary, our study showed that both CD4 and CD8 T cells showed similar immune response when stimulated with SEB, though as expected, SEB‐specific CD8 T cells were more degranulating while CD4 T cells were more cytokine producing.…”

Section: Discussionsupporting

confidence: 85%

“…It has also been hypothesized that CD4 T cells contribute to the tolerance of abacavir in HLA-B*5701 patients, leading to the high number of false positives through HLA screening. 22 On the contrary, our study showed that as well as those of CFSE low CD4 and CD8 T cells (plot d). Significance of the difference between different groups is given in the upper section of the plots both CD4 and CD8 T cells showed similar immune response when stimulated with SEB, though as expected, SEB-specific CD8 T cells were more degranulating while CD4 T cells were more cytokine producing.…”

Section: Discussioncontrasting

confidence: 53%

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Comparison of abacavir‐specific effector and proliferating functions of CD8 T cells in abacavir‐treated HIV‐1 patients

Faridi

Patel

Dharmani‐Khan

et al. 2020

Microbiology and Immunology

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Susceptibility to abacavir hypersensitivity (ABH) in HIV‐1‐positive patients is strongly linked to the carriage of HLA‐B*57:01 and the potential mechanism includes drug‐specific activation of cytokine producing CD8 T cells exclusively in individuals carrying HLA‐B*57:01. Here, we report a detailed characterization of abacavir‐induced functional response of CD8 T cells in HLA‐B*57:01pos individuals. Peripheral blood mononuclear cells (PBMNCs) from HLA‐B*57:01posABHpos and HLA‐B*57:01negABHneg individuals were stimulated with abacavir. Multicolor flow cytometry was performed to assess the cytokine (IFNγ) production and degranulation (CD107a expression) after 6–18 hr culture and to enumerate proliferating CD4/CD8 T cells by culturing carboxyfluorescein diacetate succinimidyl ester‐loaded PBMNCs for 7 days. CD8 T cells from HLA‐B*57:01posABHpos individuals were multifunctional: proliferating, IFNγ producing, degranulating (CD107apos), and both degranulating and IFNγ producing (CD107aposIFNγpos). Degranulating CD8 T cells in general and both degranulating and IFNγ producing CD8 T cells in particular dominated abacavir‐specific immune response. All functional responses were partially blocked by addition of HLA‐B*57:01‐reactive Bw4 mAb, but not by non‐HLA‐B*57:01‐reactive Bw6 mAb. In conclusion, the study demonstrates that abacavir‐specific CD8 T‐cell‐restricted immune response in HLA‐B*57:01posABHpos HIV‐1 patients has multiple effector and proliferating functions, where the primary effector response appears to be the release of cytolytic granules. The findings have implications for immunotherapy of HLA‐related drug hypersensitivities.

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Section: Discussionsupporting

confidence: 85%

Section: Discussioncontrasting

confidence: 53%

Comparison of abacavir‐specific effector and proliferating functions of CD8 T cells in abacavir‐treated HIV‐1 patients

Faridi

Patel

Dharmani‐Khan

et al. 2020

Microbiology and Immunology

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“…Hence, some who carry the HLA-B*57:01 allele do not have adverse drug reactions to abacavir. This discovery also allows for future studies in the field of T-cell-mediated drug tolerance [2].…”

Section: Pharmacogenomicsmentioning

confidence: 91%

The 10th International Congress on Cutaneous Adverse Drug Reactions, Shimane, Japan, 2018: Focus on New Discoveries

et al. 2019

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“…CD28 costimulation promotes T cell proliferation, cytokine production, and T cell survival (74). In a transgenic mouse model for HLA-B*57:01linked abacavir hypersensitivity, CD80 on DCs are upregulated upon CD4+ T cell depletion (likely including Tregs), resulting in an adverse immune response (52,53). To further assess the effect of blocking this pathway on DTH, mice with antibodies targeting CD28 or CD80 inhibited the accumulation of reactive CD8+PD-1+ T cells in the lymph nodes, dampening the immune response to abacavir.…”

Section: Cd28mentioning

confidence: 99%

The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

Hsu

et al. 2021

Front. Immunol.

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The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

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Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration

Cited by 14 publications

References 16 publications

Comparison of abacavir‐specific effector and proliferating functions of CD8 T cells in abacavir‐treated HIV‐1 patients

Comparison of abacavir‐specific effector and proliferating functions of CD8 T cells in abacavir‐treated HIV‐1 patients

The 10th International Congress on Cutaneous Adverse Drug Reactions, Shimane, Japan, 2018: Focus on New Discoveries

The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

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