Characterisation of the clinical and activated T cell response to repeat delayed-type hypersensitivity skin challenges in human subjects, with KLH and PPD, as a potential model to test T cell-targeted therapies

Belson, Alexandra; Schmidt, Tim; Fernando, Disala; Hardes, Kelly; Scott, Nicola; Brett, Sara; Clark, Deborah A.; Oliveira, João J.; Davis, Bill; McHugh, SM; Stone, John

doi:10.1007/s00011-016-0923-4

Cited by 15 publications

(43 citation statements)

References 22 publications

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“…This report provides instructions for a single intradermal deposition of 2 TU, and optionally two parallel depositions (2 x 2 TU), which may require additional ethical approval. However, other studies have used 10 TU, which increase the likelihood of a strong skin reaction 10 21 . During the SB induction step, small stepwise increases in the negative pressure will reduce the risk of hemorrhage and blister rupture.…”

Section: Discussionmentioning

confidence: 99%

“…The aseptic puncture technique prevents microbial contamination and avoiding contact between the puncture needle and the dermal blister floor reduces impurities of debris or resident skin cells. However, some researchers prefer to harvest SB fluid by applying a rolling pressure to the punctured blister 10 . It may be necessary to puncture the septa within the blister.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, there has been an increasing interest in the SB method for the study of in vivo immune responses other than diseases restricted to the skin 10 11 . The study of the adaptive immunity in humans is limited by the fact that the cells and cytokines of interest are sampled from peripheral blood because an invasive sampling of the lymph node or gastrointestinal mucosal tissue may be unacceptable and unethical.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, the relevant ex vivo analysis of the cells and cytokines isolated by SB is exemplified . Phenotypical and functional characteristics of PPD-specific T-cells obtained by the SB method are thoroughly described elsewhere 2 10 11 16 17 18 19 . This report aims to discuss the practical and immunological aspects of the methodology to ease the application of this technique by other research groups.…”

Section: Introductionmentioning

confidence: 99%

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A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Holm

Vukmanovic‐Stejic

Blauenfeldt

et al. 2018

JoVE

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Cutaneous antigen-recall models allow for studies of human memory responses in vivo. When combined with skin suction blister (SB) induction, this model offers accessibility to rare populations of antigen-specific T-cells representative of the cellular memory response as well as the cytokine microenvironment in situ.This report describes the practical procedure of a cutaneous recall, an SB induction, and a harvest of antigen-specific T-cells. To exemplify the method, the tuberculin skin test is used for antigenic recall in individuals who, prior to this study, underwent a Bacillus Calmette-Guérin vaccination against an infection with Mycobacterium tuberculosis. Finally, examples of multiplex and flow cytometric analyses of SB specimens are provided, illustrating high fractions of antigen-specific polyfunctional CD4+ T-cells available by this sampling method compared with cells isolated from the blood.The method described here is safe and minimally invasive, provides a unique opportunity to study both innate and adaptive immune responses in vivo, and may be beneficial to a broad community of researchers working with cell-mediated immunity and human memory responses, in the context of vaccine development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Holm

Vukmanovic‐Stejic

Blauenfeldt

et al. 2018

JoVE

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“…In particular, the Montoux test (MT) is a very elegant in vivo model with which to study cutaneous T cell memory by provoking the formation of blisters at the site of intradermal injection of purified protein derivative (PPD) tuberculin in healthy individuals who had been previously vaccinated with BCG. With this method, PPD-specific and allergen-specific CD4+ CLA+ Tcm and Tem were found to accumulate in the skin and suction blister fluids of the MT reaction and at the site of repeated DTH challenge with PPD and keyhole limpet hemocyanin (KLH) [45,46]. T cell infiltration occurred with specific kinetics, until resolution of the inflammatory reaction [47], thus underscoring that cutaneous immunity relies on the activity of distinct memory T cell subsets responding to recall Ag.…”

Section: Cd4+ T Cells In the Skin Can Be Put To Workmentioning

confidence: 99%

Modulation of CD4+ T Helper Cell Memory Responses in the Human Skin

Padovan

2017

Int Arch Allergy Immunol

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Immunological memory is defined as the capacity to mount faster and more effective immune responses against antigenic challenges that have been previously encountered by the host. CD4+ T helper (Th) cells play central roles in the establishment of immunological memory as they assist the functions of other leukocytes. Th cells express polarized cytokine profiles and distinct migratory and seeding capacities, but also retain a certain functional plasticity that allows them to modulate their proliferation, activity, and homing behaviour upon need. Thus, in healthy individuals, T cell immunomodulation fulfils the task of eliciting protective immune responses where they are needed. At times, however, Th plasticity can lead to collateral tissue damage and progression to autoimmune diseases or, conversely, incapacity to reject malignant tissues and clear chronic infections. Furthermore, common immune players and molecular pathways of diseases can lead to different outcomes in different individuals. A mechanistic understanding of those pathways is therefore crucial for developing precise and curative medical interventions. Here, I focus on the skin microenvironment and comprehensively describe some of the cellular and molecular determinants of CD4+ T cell memory responses in homeostatic and pathological conditions. In discussing the cellular network orchestrating cutaneous immunity, I comprehensively describe the bidirectional interaction of skin antigen-presenting cells and mononuclear phagocytes with Th17 lymphocytes, and examine how the outcome of this interaction is influenced by endogenous skin molecules, including sodium salts and neuropeptides.

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Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

Ellis

Marks

Srinivasan

et al. 2020

Clin Pharma and Therapeutics

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Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 + and CD8 + T cells. We describe the engineering and first-inhuman clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3 + cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/ kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3 + and CD3 + T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

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Characterisation of the clinical and activated T cell response to repeat delayed-type hypersensitivity skin challenges in human subjects, with KLH and PPD, as a potential model to test T cell-targeted therapies

Cited by 15 publications

References 22 publications

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Modulation of CD4+ T Helper Cell Memory Responses in the Human Skin

Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

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Characterisation of the clinical and activated T cell response to repeat delayed-type hypersensitivity skin challenges in human subjects, with KLH and PPD, as a potential model to test T cell-targeted therapies

Cited by 15 publications

References 22 publications

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

A Suction Blister Protocol to Study Human T-cell Recall Responses <em>In Vivo</em>

Modulation of CD4+ T Helper Cell Memory Responses in the Human Skin

Depletion of LAG‐3+ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781

Contact Info

Product

Resources

About

Depletion of LAG‐3⁺ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781