Short Course of Lolium Perenne Peptides (LPP) Immunotherapy Deletes Circulating IL-4+IL-21+ T follicular helper cells and Induces FoxP3+ T follicular regulatory cells: A Randomized Controlled Trial

Sharif, Hanisah; Sharif, Hanisah

RATIONALE: Allergen peptides are considered a safer alternative for immunotherapy due to their reduced capacity to bind to IgE and elicit anaphylaxis. IgE production by B cells requires signals from T follicular helper (Tfh) cells. This cellular interaction is tightly controlled by T follicular regulatory (Tfr) cells. We hypothesized that 3-weeks treatment with subcutaneous peptide hydrolysates from Lolium Perenne (LPP) is effective and supresses pro-allergic IL-4⁺, IL-21⁺ and dual IL-4⁺IL-21⁺ Tfh cells whilst at the same time inducing ‘protective’ Tfr cells.

METHODS: In a randomized controlled trial, participants received LPP(n=22) or placebo(n=11) for 3 weeks. Circulating allergen-driven CD4⁺CXCR5⁺PD-1⁺Tfh, IL-4⁺/IL-21⁺Tfh, FoxP3⁺Tfr, FoxP3⁺Treg cells and sIgE levels were enumerated before (V2), and after treatment (V6) and at the end of the pollen season (V8).

RESULTS: Peak-seasonal symptom scores were lower in LPP compared to placebo-treated group(P<0.05). Circulating pro-allergic IL-4⁺Tfh, IL-21⁺Tfh and dual-positive IL-4⁺IL-21⁺Tfh cells as well as IL-4⁺Th2 cells were decreased in LPP compared to placebo-treated group at V6(all,P<0.01). This reduction persisted at V8(P<0.05). Conversely, circulating FoxP3⁺Tfr and suppressive CTLA4⁺Tfr cells were increased in the LPP group at V6(all,P<0.01) and remained elevated at V8(P<0.01). In addition, FoxP3⁺Treg cells were increased in LPP-treated group at V6(P<0.05). Suppressive and functional GARP⁺ and SATB1^-Treg cells were also induced in LPP-treated group at V6(P<0.05) and at V8(P<0.05). No changes were observed in placebo-treated participants.

CONCLUSIONS: For the first time, we showed that a short-course of LPP immunotherapy suppressed pro-allergic IL-4⁺ and IL-21⁺Tfh cells and induced Tfr and Treg cells in peripheral blood in association with the observed clinical benefit.