Intralymphatic immunotherapy improves grass pollen allergic rhinoconjunctivitis: A 3-year randomized placebo-controlled trial.

BACKGROUND: Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed. OBJECTIVE: In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT). METHODS: Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). A novel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen. RESULTS: A total of 36 patients were included. Log10-transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P = .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P < .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found. CONCLUSIONS: ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. A booster injection had no additional effect.

Intralymphatic immunotherapy for mountain cedar pollinosis: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Allergen immunotherapy can provide long-term benefits, including symptomatic relief and reduced disease progression, but it requires a lengthy regimen that presents barriers to patient adherence. Thus, there is a need for improved approaches to immunotherapy. Recently, several clinical trials have reported successful results from intralymphatic immunotherapy. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of intralymphatic immunotherapy for allergies caused by mountain cedar pollen in a proof-of-concept study. METHODS: A total of 21 patients with allergic rhinoconjunctivitis because of mountain cedar pollen were randomized to receive 3 monthly intralymphatic injections of allergenic extract or placebo before the 2018-2019 mountain cedar pollen season. Safety was monitored during treatment to the end of the pollen season using structured and spontaneous reports. Clinical efficacy information was collected using a daily electronic diary of symptoms and allergy medication. Allergen-specific serum immunoglobulin E was assessed before treatment and at the end of the study. RESULTS: There were no serious adverse events or systemic reactions in either group. A total of 4 patients experienced mild injection-site reactions. Patients receiving intralymphatic immunotherapy experienced a significant improvement in allergy symptoms and medication use relative to patients receiving placebo (P < .001), and the active treatment group had lower average total combined scores on 20 of 27 days during the peak pollen season (P < .05). There was no significant difference among groups in changes to mean mountain cedar-specific serum immunoglobulin E levels. CONCLUSION: In this proof-of-concept trial, intralymphatic immunotherapy was well tolerated and improved the symptoms and medication use associated with allergic rhinoconjunctivitis caused by mountain cedar pollen. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov under the registration number NCT03682965 before the enrollment of the first subject.

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route.

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

Novel strategies for the treatment of grass pollen-induced allergic rhinitis.

INTRODUCTION: Allergic rhinitis (AR) affects over 20% of the population of Europe and the United States. Allergen immunotherapy (AIT) is currently the only form of treatment that affects symptoms and modifies the progression of disease. Established forms of AIT include subcutaneous (SCIT) and sublingual (SLIT) immunotherapy and are widely effective, yet only 2-9% of eligible patients undergo therapy, likely due to the long duration of treatment. As a result, novel, faster forms of AIT are currently under development. AREAS COVERED: This article provides an overview of AR and summarises the efficacy and mechanisms of established forms of AIT, highlighting the current drawbacks. We discuss novel strategies of AIT that have been developed in an attempt to tackle these limitations, including epicutaneous, intradermal and intralymphatic immunotherapy (ILIT), focusing on ILIT, the treatment that has been most comprehensively assessed. EXPERT OPINION: Current strategies to treat AR suffer from a poor safety profile and, importantly, lack of adherence. ILIT is a faster and safer form of AIT, with a treatment regime of only 12 weeks. Further validation is required, but ILIT, with its short and comparatively inexpensive protocol, has the potential to offer disease-modifying therapy to a larger number of patients.

Alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy.

BACKGROUND: Some alternative products instead of immunotherapy are used in patients with allergic rhinitis (AR). METHODS: In this paper, alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy are reviewed. RESULTS: Alternative products and methods used instead of immunotherapy are tea therapy, acupuncture, Nigella sativa, cinnamon bark, Spanish needle, acerola, capsaicin (Capsicum annum), allergen-absorbing ointment, and cellulose powder. N. sativa has been used in AR treatment due to its anti-inflammatory effects. N. sativa oil also inhibits the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The beneficial effects of N. sativa seed supplementation on the symptoms of AR may be due to its antihistaminic properties. To improve the efficacy of immunotherapy, some measures are taken regarding known immunotherapy applications and alternative routes of intralymphatic immunotherapy and epicutaneous immunotherapy are used. CONCLUSION: There are alternative routes and products to improve the efficacy of immunotherapy.

Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.

BACKGROUND: Allergen-specific immunotherapy is the only causative treatment of IgE-mediated allergic disorders. The most common administration route is subcutaneous, which may necessitate more than 50 allergen injections during 3 to 5 years. Recent evidence suggests that direct intralymphatic injections could yield faster beneficial results with considerably lower allergen doses and markedly reduced numbers of injections. OBJECTIVE: To evaluate the effects of intralymphatic allergen-specific immunotherapy in pollen-allergic patients. METHODS: In an open pilot investigation followed by a double-blind, placebo-controlled study, patients with allergic rhinitis were treated with 3 intralymphatic inguinal injections of ALK Alutard (containing 1000 SQ-U birch pollen or grass pollen) or placebo (ALK diluent). Clinical pre- and posttreatment parameters were assessed, the inflammatory cell content in nasal lavage fluids estimated, and the activation pattern of peripheral T cells described. RESULTS: All patients tolerated the intralymphatic immunotherapy (ILIT) treatment well, and the injections did not elicit any severe adverse event. Patients receiving active treatment displayed an initial increase in allergen-specific IgE level and peripheral T-cell activation. A clinical improvement in nasal allergic symptoms upon challenge was recorded along with a decreased inflammatory response in the nose. In addition, these patients reported an improvement in their seasonal allergic disease. No such changes were seen in the placebo group. CONCLUSIONS: Although this study is based on a limited number of patients, ILIT with grass-pollen or birch-pollen extracts appears to reduce nasal allergic symptoms without causing any safety problems. Hence, ILIT might constitute a less time-consuming and more cost-effective alternative to conventional subcutaneous allergen-specific immunotherapy.

[Magnetic laser therapy in combination with lymphotropic drugs administration in treating teenagers with common forms of tuberculosis]. / Magnitolazerterapiia v sochetanii s limfotropnym vvedeniiem khimiopreparatov pri lechenii podrostkov s rasprostranennymi formami tuberkuleza.

The paper shows the efficiency of combined use of magnetic laser therapy (MLT) and lymphotropic drug therapy in 40 teenagers with common forms of tuberculosis. The use of laser makes it possible to modify methods of regional lymphotropic therapy, to prolong its use and increase indications for it. MLT in combination with lymphotropic drug therapy accelerates positive changes and hence enhances the efficiency of tuberculosis treatment.

Local application of capsaicin into the draining lymph nodes attenuates expression of adjuvant-induced arthritis.

Adjuvant-induced experimental arthritis (AA) was examined in adult male Lewis rats after isolated capsaicin (CAPS)-induced loss of small, nonmyelinated, afferent fibers in lymph nodes draining the site of adjuvant challenge. AA was induced by intradermal injection of Freund's complete adjuvant (CFA) into the subplantar area of the right hind paw. Controls received similar injections of mineral oil, the vehicle for CFA. One day later, half of the CFA-treated rats and half of the mineral oil-treated rats received injections of CAPS bilaterally into the draining lymph nodes (DLN). The DLN of remaining rats were injected with 50:50 ethanol/sterile physiological saline, the vehicle for CAPS. This paradigm resulted in four groups designated: CFA/CAPS, CFA/vehicle, vehicle/CAPS and vehicle/vehicle. Since substance P (SP) is present in small, nonmyelinated, afferent fibers, the target of the neurotoxin, CAPS, a radioimmunoassay specific for SP was used to verify the loss of these nerve fibers. CAPS injections into the DLN resulted in a loss in SP concentration in the DLN, with no depletion of SP in the spleen or sciatic nerve. These findings support the destruction of SP-containing nerves, which we interpret as verification of the selective loss of small, non-myelinated afferent nerves in the DLN with no significant spread of the neurotoxin to the nearby sciatic nerves which supply small, nonmyelinated, afferent fibers to the hind limb joints. Also, preservation of SP content in spleen indicates CAPS did not circulate via the lymphatic drainage. No chronic inflammation was observed in the fore or hind limbs from rats treated with the vehicle for CFA (vehicle/vehicle, vehicle/CAPS) at any time during the study. In CFA/vehicle-treated rats, bilateral, symmetrical inflammation of the hind limbs was apparent 14 days after challenge with CFA, and became progressively more inflamed through day 20. In contrast, hind limb inflammation in arthritic rats treated with CAPS was not symmetrical. On days 14 and 20 after challenge with CFA, the inflammatory response in the left hind limb, contralateral to the site of CFA injection, was significantly (p < 0.05) attenuated compared with the response seen on the right side of CFA/CAPS-treated rats, and with the response seen in left hind limb of CFA/vehicle-treated animals. In fact, the mean dorsoplantar width of contralateral hind limbs from CFA/CAPS-treated animals was not different from that measured in non-AA control groups. These findings support a role for small, nonmyelinated, sensory nerves that modulate immune responses in DLN in the development and progression of AA in Lewis rats.

[Results of application of endolymphatic polychemotherapy and local supra-high frequency hyperthermia in comprehensive treatment of rectal cancer]. / Rezul'taty primeneniia éndolimfaticheskoi polikhimioterapii i lokal'noi SVCH-gipertermii v komplekse lecheniia raka priamoi kishki.

The treatment efficacy of a widespread cancer of recti using neoadjuvant endolymphatic polychemotherapy and local suprahigh frequency hyperthermy in a radically operated patients was studied up. In patients without regional metastases the five-year survival index have increased from 63 to 81%, and the recurrencies occurrence frequency have lowered from 20 to 10%. The method proposedhas small efficacy in patients with metastases in regional lymph nodes.

[The arteriolymphatic administration of antibiotics in treating patients with suppurative-inflammatory diseases of the abdominal cavity organs]. / Arteriolimfaticheskoe vvedenie antibiotikov pri lechenii bol'nykh s gnoino-vospalitel'nymi zabolevaniiami organov briushnoi polosti.

Experimental study of pharmacokinetics of Gentamicin was carried out in 23 dogs. Three different modes of its intralymphatic administration were used: intranodular inguinal, lymphotropic retroperineal and arterio-lymphatic. It has been established, that arterio-lymphatic mode of introduction of antibiotics (as well as regional endolymphatic and lymphotropic) warrants high concentration of antibiotics in venous blood and lymph. The peculiarity of arteriolymphatic administration is regional effect of accumulation of the antibiotic in organs and tissues of abdominal cavity of corresponding arterial region. Arteriolymphatic infusions of antibiotics have been introduced into complex of drug treatment of patients with pyogenic and inflammatory disorders of abdominal organs. The clinical testing has revealed high curative effect of this made of antibiotics administration.

[Intensive intralymphatic and lymphotropic therapy in children]. / Intensivnaia éndolimfaticheskaia i limfotropnaia terapiia u detei.

Study of the effect of endolymphatic therapy with antibiotics and antioxidants on lipid peroxidation and endotoxicosis level in children in critical state showed that endolymphatic infusion of nonenzymatic antioxidants (vitamin E, unithiol) and wide-spectrum antibiotics noticeably reduced the activity of free-radical lipid peroxidation and accelerated detoxication in comparison with the control group.

[Endolymphatic polychemotherapy with local ultra high frequency hyperthermia for the combined treatment of invasive rectal cancer]. / Endolimfaticheskaia polikhimioterapiia s lokalnoi SVCh-gipertermiei v komplekse lecheniia rasprostranennykh form raka priamoi kishki.

The results of treatment of diffuse forms of rectal cancer with the use of a preoperative course of endolymphatic polychemotherapy (fluorouracil and platidiam) and local SHF-hyperthermia are presented. The most pronounced effect of treatment was noted in patients with metastases to the regional lymph nodes. The method suggested is effective in treatment of all the types of adenocarcinoma. All the patients survived for 2 years.

[Regional lymphotropic therapy]. / Regional'naia limfotropnaia terapiia.

The article deals with the results of experimental studies on 10 male and female dogs conducted under intrapleural hexenal anaesthesia. The rate of elimination of the lymphotrophic dye indigo carmine from the subserous depot in the wall of the gallbladder, stomach, and small intestine under normal conditions and in regional stimulation of lymphatic drainage was studied. The rate of total elimination increased 2.4 times in stimulation. On the grounds of these studies, regional lymphotrophic therapy was conducted in 417 patients treated at a general surgical hospital. As the result of this treatment the inflammatory process was arrested in a shorter time, the laboratory indices were normalized more rapidly, and the term of treatment was shorter than in patients of the control group.

[An experimental validation of the endolymphatic administration of pharmacological preparations for stimulating intestinal peristalsis in emergency surgery on the abdominal cavity]. / Eksperimental'noe obosnovanie éndolimfaticheskogo vvedeniia farmakologicheskikh preparatov dlia stimuliatsii peristal'tiki kishechnika v ékstrennoi khirurgii briushnoi polosti.

Experiments were conducted on 75 rabbits to study the efficacy of endolymphatic administration of aceclidine, obsidan, and cerucal for stimulation of the intestine in its experimental paresis. The stimulating effect of the pharmacological agents was found to be of a longer duration in endolymphatic that in intravenous administration. This allowed endolymphatic pharmacological stimulation of the intestine to be suggested for the use in abdominal surgery.

[The ultraviolet irradiation of autologous blood and endolymphatic antibiotic therapy in treating pneumonia in patients with craniocerebral trauma]. / Ul'trafioletovoe obluchenie autokrovi i éndolimfaticheskaia antibiotikoterapiia pri lechenii pnevmonii u bol'nykh s cherepno-mozgovoi travmoi.

On the basis of analysis of 50 cases of craniocerebral injury complicated by pneumonia, the authors prove the efficacy of including ultraviolet irradiation of autologous blood and endolymphatic antibiotic therapy in the complex of therapeutic measures. The mortality and the period of in-hospital treatment of this group of patients reduced.