Strengthening the case for intralymphatic immunotherapy.

PURPOSE OF REVIEW: Intralymphatic immunotherapy (ILIT) is a promising novel method of immunotherapy, that is short and convenient, and may be very effective. Results have been varied, and efforts to unravel the real value of the treatment are ongoing. Methods used to assess the effect in clinical trials have been so varied that it is difficult to compare studies with each other. RECENT FINDINGS: Some advances have been made; the importance of injecting into the lymph node has been illustrated, and treatment with a range of medicines has proven to be successful. In meta-analyses the treatment has been shown to have no serious side effects and to be an effective short term desensitizing agent. Now it remains to be shown that ILIT also has long-term effects of tolerance. Preliminary data suggest that there is a long-term effect. SUMMARY: Injecting allergen directly into a lymph node strengthens the protective immune response. ILIT is safe and induces desensitization and very likely also induces tolerance. Compliance will improve compared with other treatment forms. If ILIT holds its promise, it will become an attractive option for patients with allergy.

Intralymphatic immunotherapy with tyrosine-adsorbed allergens: a double-blind, placebo-controlled trial.

BACKGROUND: Most previous studies used aluminum hydroxide-absorbed allergen extracts in evaluating the potential therapeutic roles of intralymphatic allergen-specific immunotherapy (ILAIT). In this study, we evaluated the therapeutic efficacy and safety of ILAIT with L-tyrosine-adsorbed allergen extracts of Dermatophagoides farinae, D. pteronyssinus, cat, dog, or mixtures thereof, in patients with allergic rhinitis induced by these allergens. METHODS: In this randomized, double-blind, placebo-controlled trial, study subjects received three intralymphatic injections of L-tyrosine-adsorbed allergen extracts (active group) or saline (placebo group) at 4-week intervals. RESULTS: Although ILAIT reduced daily medication use and skin reactivity to HDM and cat allergens at 4 months after treatment, overall symptom score on a visual analog scale (VAS), sinonasal outcome test-20 (SNOT-20), rhinoconjunctivitis quality of life questionnaire (RQLQ), daily symptom score (dSS), daily medication score (dMS), daily symptom medication score (dSMS), nasal reactivity to HDM allergen, and basophil activity to HDM, cat, and dog allergens at 4 months and 1 year after treatment were similar between the treatment and control groups. Intralymphatic injection was more painful than a venous puncture, and pain at the injection site was the most frequent local adverse event (12.8%); dyspnea and wheezing were the most common systemic adverse events (5.3%). CONCLUSIONS: ILAIT with L-tyrosine-adsorbed allergen extracts does not exhibit profound therapeutic efficacy in allergic rhinitis and can provoke moderate-to-severe systemic reactions and cause pain at the injection site. TRIAL REGISTRATION: clinicaltrials.gov: NCT02665754; date of registration: 28 January 2016.

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system.

Lymph node (LN) metastasis is thought to account for 20-30% of deaths from head and neck cancer. The lymphatic drug delivery system (LDDS) is a new technology that enables the injection of drugs into a sentinel LN (SLN) during the early stage of tumor metastasis to treat the SLN and secondary metastatic LNs. However, the optimal physicochemical properties of the solvent used to carry the drug have not been determined. Here, we show that the osmotic pressure and viscosity of the solvent influenced the antitumor effect of cisplatin (CDDP) in a mouse model of LN metastasis. Tumor cells were inoculated into the proper axillary LN (PALN), and the LDDS was used to inject CDDP solution into the subiliac LN (SiLN) to treat the tumor cells in the downstream PALN. CDDP dissolved in saline had no therapeutic effects in the PALN after it was injected into the SiLN using the LDDS or into the tail vein (as a control). However, CDDP solution with an osmotic pressure of ~ 1,900 kPa and a viscosity of ~ 12 mPa⋅s suppressed tumor growth in the PALN after it was injected into the SiLN using the LDDS. The high osmotic pressure dilated the lymphatic vessels and sinuses to enhance drug flow in the PALN, and the high viscosity increased the retention of CDDP in the PALN. Our results demonstrate that optimizing the osmotic pressure and viscosity of the solvent can enhance the effects of CDDP, and possibly other anticancer drugs, after administration using the LDDS.

[Intralymphatic allergen-specific immunotherapy].

An emerging method for allergen-specific immunotherapy is intralymphatic placement, which only requires three injections with intervals of four weeks. In this review, we summarise available evidence on clinical safety, biological efficacy and therapeutic outcomes. The treatment appears to be safe with only few and mild adverse reactions. The immunological activation profile is comparable to that known for subcutaneous therapy. Clinically, patients experienced fewer symptoms with less medication use with intralymphatic allergen-specific immunotherapy than with other types of immunotherapy. The number of studies is limited, and the studies have important limitations. More phase 3 studies are needed in order to make a conclusion.

Long-term effects of intralymphatic immunotherapy (ILIT) on canine atopic dermatitis.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is an established and efficacious therapy for canine atopic dermatitis (AD). In humans, intralymphatic immunotherapy (ILIT) was reported to be associated with fewer and less severe adverse effects than subcutaneous allergen immunotherapy and to be efficacious for several years after three intralymphatic injections. OBJECTIVE: To evaluate safety and effects of ILIT in a case series of dogs with (AD). ANIMALS: Fifty one privately owned dogs with AD. METHODS: Dogs received injections of 0.2 mL alum-precipitated allergen extract into the popliteal lymph nodes at monthly intervals for 3-5 months. Lesion scores, pruritus and medication scores were determined before and at three and 12 months after beginning immunotherapy, and compared in a per protocol analysis (PP) and an intention-to-treat analysis (ITT). RESULTS: Twenty two dogs completed the study and 29 dogs did not fulfil study completion criteria due to lack of a final study visit (21 of 29) or due to insufficient improvement (14 of 29). All scores improved during the study with both analyses. For pruritus and Quality of Life scores this improvement was significant with both analyses; for Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 values and medication scores only with PP. The only rare adverse effects observed included mild swelling of the lymph node post-injection and increased pruritus. CONCLUSION AND CLINICAL RELEVANCE: ILIT is safe and feasible, and provides long-lasting relief in some atopic dogs with a limited number of injections.

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.

Intralymphatic immunotherapy of pollen-induced rhinoconjunctivitis: a double-blind placebo-controlled trial.

BACKGROUND: Allergen-specific immunotherapy represents the only disease-modifying treatment for allergic diseases. We and others have previously demonstrated that intralymphatic immunotherapy (ILIT), a less time-consuming alternative to conventional subcutaneous immunotherapy (SCIT), is safe and effective. However, this has recently been disputed. The aim of this study was therefore to expand our previous trial, further assessing the safety and efficacy of ILIT. METHODS: Thirty-six patients with pollen-induced rhinoconjunctivitis were randomised to receive three intralymphatic inguinal injections of active allergen (1000 SQ-U birch- or grass-pollen) or placebo. Clinical effects, safety and circulating immunological markers were assessed before, 4 weeks after treatment and at the end of the consecutive pollen season. RESULTS: No moderate or severe reactions were recorded following ILIT. Patients receiving active ILIT experienced a significant improvement in self-recorded seasonal allergic symptoms, as compared to placebo (p = 0.05). In a subgroup of these patients ("improved"), a reduction in nasal symptoms following nasal allergen provocation was also demonstrated. No changes in total IgE or IgG4 were found. However, the affinity of allergen specific IgG4 following active treatment was significantly increased, as compared to non-improved patients (p = 0.04). This could be correlated with clinical improvement, on an individual level. CONCLUSIONS: This double-blinded placebo-controlled study confirms that ILIT is a safe and effective treatment for pollen-induced rhinoconjunctivitis, markedly reducing seasonal allergic symptoms. TRIAL REGISTRATION: EudraCT: 2009-016815-39.

Lymphotropic administration of photosensitizer as a model of target therapy of testicle inflammation: Experimental and clinical data.

BACKGROUND: The existence of zones of humoral skin-subskin tissue linkage with internal organs as well as the possibility of targeted administration of preparation into the affected organs were studied. METHODS: An experimental study of preparation and distribution in the bodies of mice was held by both intravenous and lymphotropic methods of administration. By means of detection with a photosensitizer (as a marker), the study was conducted on healthy mice and mice with testicle inflammation. Based on the experimental results, the study has been implemented into the clinical practice of treatment of acute inflammatory diseases of testicle and its epididymis. Patients were administered antibiotics either by the lymphotropic method, or by traditional methods. RESULTS: The concentration of the preparation, administered by the lymphotropic method, maintained in target organs (testicles) at a high level for a longer time, while the intravenous injections provided fast achievement of high concentrations. Moreover there was a lower level of accumulation of the photosensitizer in parenchymal organs after subcutaneous (lymphotropic) administration. CONCLUSIONS: The presence of humoral connection of certain areas of skin and subcutaneous tissue with testicles and their epididymis was proved. It was found that the lymphotropic administration leads to earlier clinical improvement and normalization of laboratory indices, and, thus, to significant reduction in hospital stay. Such results open the possibility of targeted drug delivery to the diseased organs. In perspective, the method may be used in treating patients not only in urology, but also in surgery, as well as for many acute, chronic or cancer diseases.

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.

Sclerotherapy with bleomycin does not adversely affect facial nerve function in children with cervicofacial cystic lymphatic malformation.

BACKGROUND AND PURPOSE: Sclerotherapy with bleomycin sulfate (BS) is currently used in the management of cervicofacial cystic lymphatic malformations in children. Neurotoxic adverse effects of BS after intraventricular or intracavitary administration have been reported; however, the effects of intralesionally administered BS on the adjacent peripheral neural structures have not been previously investigated. The authors conducted a clinical experimental study to evaluate facial nerve function in children who have undergone BS sclerotherapy for cervicofacial cystic lymphatic malformation. MATERIALS AND METHODS: Twelve patients who underwent BS sclerotherapy for cervicofacial lymphatic malformation were included in the study. The hospital records were reviewed, and the following data were recorded: age at admission and at the time of motor nerve conduction study (MNCS) and electromyography (EMG) study, sex, time elapsed between sclerotherapy and the EMG study, and the outcome. The MNCS/EMG study was performed by neurologists blinded to the side of sclerotherapy. Bilateral facial MNCS and needle-EMG study of the orbicularis oris muscle on the treated side were performed. The previously treated and untreated sides constituted the study and control groups, respectively. In the MNCS, compound muscle action potential (CMAP) amplitude and distal latencies were recorded from the orbicularis oculi and orbicularis oris muscles on both sides, and needle-EMG of the orbicularis oris muscle was performed on the treated side. RESULTS: The male-to-female ratio was 2, and age at the time of sclerotherapy ranged from 1 month to 16 years (median, 19.5 months). The lymphatic malformations were located in the right submandibular (n = 5), left submandibular (n = 6), and in the right buccal (n = 1) areas. Bleomycin sulfate was injected 1 to 4 times, and the time elapsed between injections varied from 1 to 6 months. The results of sclerotherapy were excellent, with residual disease observed in only 1 patient. The MNCS/EMG study was performed 6 months to 10 years after completion of sclerotherapy, and ages of the patients at the time of the study ranged from 4 to 17 years. Side-to-side CMAP amplitude difference did not exceed 50% for orbicularis oculi and orbicularis oris muscles. The mean CMAP amplitude of orbicularis oculi and orbicularis oris muscles on the treated and untreated sides (1219.0 +/- 842.0 vs 1202.4 +/- 923.8 microV and 1866.3 +/- 911.5 vs 1921.0 +/- 910.0 microV, respectively) did not differ between groups (P = .76 and P = .80). Distal latencies recorded from orbicularis oculi and orbicularis oris muscles on treated and untreated sides (2.64 +/- 0.46 vs 2.68 +/- 0.47 milliseconds and 3.10 +/- 0.35 vs 3.10 +/- 0.25 milliseconds, respectively) also did not differ between groups (P = .71 and P = .80). Needle-EMG orbicularis oris muscle (n = 11) on the treated side showed normal findings at rest, and there was no spontaneous activity. During mild voluntary contraction, the amplitude and duration of motor unit action potentials were within normal limits except in one case. Interference patterns were also normal in all cases. CONCLUSION: Bleomycin sulfate did not adversely affect facial nerve function in children who underwent sclerotherapy for cervicofacial cystic lymphatic malformation when it was applied according to our protocol.

Immunologic and clinical effects of injecting mature peptide-loaded dendritic cells by intralymphatic and intranodal routes in metastatic melanoma patients.

PURPOSE: A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells. EXPERIMENTAL DESIGN: Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-gamma, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8(+) lymphocytes and delayed-type hypersensitivity tests. RESULTS: Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin-pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months. CONCLUSIONS: Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.

Rationale for superficial injection techniques in lymphatic mapping in breast cancer patients.

One of the most avidly debated issues in lymphatic mapping is where the tracers are best deposited in patients with breast cancer. The four superficial approaches are easy to perform and have several other distinct advantages. They are based on the hypothesis that the entire breast parenchyma and the overlying skin drain to a common node in the axilla because of their common embryological origin. Evidence is presented that casts doubt upon the correctness of this assumption. Tracer administration close to the tumor site appears to be the safest approach for the time being. Excellent results can be obtained with this latter approach, despite the fact that it is technically more demanding.

Endolymphatic infusion: human surgical investigation and application.

The ability to influence changes within the lymphatic system, and to exert a therapeutic influence on the composition and quality of the lymph, may have a substantial impact on the therapeutic outcome in disease interventions. This report concerns our experience with endolymphatic infusion (ELI) of drugs, an approach that we have utilized in a surgical context to destroy bacteria within lymphatic vessels and lymph nodes. Experimentally, we have demonstrated that a variety of antibiotics will temporarily decrease the contractile activity of the lymphatic vessels and reduce the volume of lymph flow. Based on our initial observations, we have applied endolymphatic infusion to clinical care. ELI was evaluated in the treatment of 330 patients, utilizing protocols to alter the characteristics of lymph flow.

[Optimization of indirect endolymphatic injection of isoniazid in pulmonary tuberculosis]. / Optimizatsiia nepriamogo éndolimfaticheskogo vvedeniia izoniazida pri tuberkuleze legkikh.

The authors have substantiated and studied the use of lymphotropic (interstitial) injection of 1% isoniazid solution in the complex therapy of patients with pulmonary tuberculosis. The method provides active interstitial functioning of the diseased organ. This leads to a substantial improvement of immediate results of treatment in patients as accelerated closure of decay cavities and double cessation of bacterial isolation.

Intralymphatic immunization enhances DNA vaccination.

Although DNA vaccines have been shown to elicit potent immune responses in animal models, initial clinical trials in humans have been disappointing, highlighting a need to optimize their immunogenicity. Naked DNA vaccines are usually administered either i.m. or intradermally. The current study shows that immunization with naked DNA by direct injection into a peripheral lymph node enhances immunogenicity by 100- to 1,000-fold, inducing strong and biologically relevant CD8(+) cytotoxic T lymphocyte responses. Because injection directly into a lymph node is a rapid and easy procedure in humans, these results have important clinical implications for DNA vaccination.

[Endolymphatic therapy]. / Leczenie dolimfatyczne.

Using physiological function of lymphatic vessels and nodes and also a fact that they are a frequent place of spreading of diseases, there are attempts of endolymphatic therapy--it means drug infusions into lymphatic vessels for the purpose of penetrate lymphatic nodes engaged by disease. There are more and more attempts of using the cytostatics placed in liposomes in endolymphatic.

[The morphology of regional lymphatic nodes in lymphotropic therapy of acute otitis media]. / Morfologiia regionarnykh limfaticheskikh uzlov pri limfotropnoi terapii ostrogo srednego otita.

Lymphotropic therapy (LT) was given to rabbits with experimental acute otitis media. The response was good. Reduced vascular blood filling, edema tissue detritus, fibrin, more compact location of lymphocytes in the lymph node cortex reflected normalization of the lymph node structure and improvement of the drainage function.

[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.