Dosing intervals in intralymphatic immunotherapy

Abstract

Allergen-specific subcutaneous (SCIT) as well as sublingual (SLIT) immunotherapy both confer long-term protection against the highly prevalent IgE-mediated allergies, such as allergic rhino-conjunctivitis and asthma. As both SCIT and SLIT are both very laborious and time-consuming treatments, we and others have investigated whether the immunotherapy could be enhanced by so-called intralymphatic immunotherapy (ILIT), which aims at improving treatment efficacy and safety and to shorten treatment duration, thereby making allergen immunotherapy (AIT) more patient friendly. In the original studies made by us [1, 2] and by Cardell et al. [3], ILIT was administered three times with four-week intervals. In 2013, Witten et al. questioned the efficacy of ILIT with grass pollen, based on the results of a clinical study of their in 38 adult hayfever patients [4]. While promising immunological changes such as increased IgG4 and Treg responses were observed, they concluded that the clinical outcome was at odds with that measured by us in 165 hay-fever and 20 cat-dander allergic patients as well as in Cardell's study with 28 hay-fever patients. The protocols in these studies differed in one major point. While our and Cardell's studies used a dosing schedule of 4 weeks, Witten's study utilized a shorter dosing schedule of 2 weeks. We chose the longer time intervals based on general vaccine recommendations as they allow buildup of successive waves of allergen-specific immune responses with efficient memory B-cell formation and affinity maturation without antibody interference. Moreover, CD4 T cells compete for antigen, and highaffinity T cells have a competitive advantage [5]. Of note, no FDA-approved childhood vaccine has a shorter time interval than 4 weeks, and the official guidelines consider a vaccination 'invalid' if the time interval is shortened to less than the recommended minimum.Comparably less is known about the role of time intervals in AIT, and especially in newer methods such as ILIT. To address this question experimentally, a preclinical test in mice was run to investigate the effects of varying ILIT dosing intervals on certain characteristics of the antibody response. Groups of five female BALB/c mice were sensitized with 1 lg ovalbumin (OVA) adsorbed to aluminium hydroxide by 4 weekly subcutaneous (s.c.) injections. Three weeks later, the mice received ILIT injections with 10 lg OVA into the inguinal lymph nodes [6]. The ILIT was repeated for a total of three injections, the time interval between each injection being one, two or four weeks (Fig. 1a). ILIT preparations with OVA were made with aluminium hydroxide [6,7] as this was the adjuvant also used in the clinical ILIT trials [1-4]. Blood was collected from tail veins at different time points during the study. OVA-specific IgG 1 , IgG 2a and IgE in serum as well as the OVA-specific affinity of IgG were measured at different time points by means of ELISA.Sensitization caused only a weak induction of anti-OVA IgG 1 a barely measurable induction of IgG 2a , but ...

IgG4 but no IgG1 antibody production after intralymphatic immunotherapy with recombinant MAT‐Feld1 in human

“…We have presented preclinical and clinical data describing intralymphatic immunotherapy (ILIT) with a recombinant allergen Feld1 fused to the 12‐mer HIV‐derived translocation sequence (GYGRKKRRQRRR) and to a part of the human invariant chain . This modular antigen transporter Feld1 (MAT‐Feld1) is efficiently taken up by antigen‐presenting cells .…”

Potential Cost Savings by Switching from Subcutaneous to Intralymphatic Insect Venom Immunotherapy

“…Since ILIT uses only 10% of the dose of SCIT, we may assume that anaphylaxis occurs 10 times less with ILIT than with SCIT due to the immunological response and the absence of mast cells in the lymph nodes. Indeed, studies have shown fewer adverse events [20][21][22][23]30] and less likelihood of anaphylaxis [35][36][37] with ILIT than with SCIT.…”

Intralymphatic Immunotherapy : A Novel Route to Ameliorate Allergic Rhinitis Due to Pollen

“…They found no clinical benefits from active ILIT. It has been debated that the short interval was not enough to make the immune system mature for the next injection compared with the need for intervals when vaccinating against infectious diseases [50]. It has also been suggested that this might have to do with too high a dose as the allergen may accumulate on shorter intervals.…”

“…Furthermore, when the intervals were narrowed to only two weeks and ILIT was administered three or six times, the clinical effect failed. It has been argued that the dosing interval between ILIT is essential [50,89]. However, narrowing the interval may also entail a higher dose.…”