Effects of Liposome-Entrapped Muramyl Tripeptide Phosphatidylethanolamine (L-MTP-PE) on the Tumor Growth and Survival of Mice Bearing Syngeneic Tumor in Combination with a Chemotherapeutic or Immunomodulatory Agent.

Antitumor activities of L-MTP-PE (Liposome entrapped myuramyl tripeptide phosphatidylethanolamine) in the combination treatment with chemo- or immune-therapeutic antitumor agents against various syngeneic tumors were tested.Against Meth A fibrosarcoma solid tumor system, L-MTP-PE showed slight but statistically significant elongation of survival days against 5-FU monotherapy in spite of its non-effect on tumor growth, when combined with 5-FU. Against liver metastasis model of M5076 carcinoma, L-MTP-PE showed a tendency of elongation of survival days by its single drug treatment, however, elongation with statistical significance was observed in the combination treatment with 5-FU in comparison with control group.These data suggest that L-MTP-PE seems to elongate the survival days of the solid tumor bearing mice and the liver metastasis model basically due to its saving effect on chemotherapeutic drug-induced immunosuppression. In the combination with an immunotherapeutic agent in mice, TNF production induced by another biological response modifier OK-432 was potentiated when primed with L-MTP-PE. L-MTP-PE also potentiate the antitumor effect of OK-432 possibly through the enhanced production of TNF-α. Combination of L-MTP-PE and OK-432 is considered to be a candidate for a new treatment model for cancer.

[Muramyldipeptide - based compounds in current medicine: focus on glucosaminylmuramyl dipeptide].

The role of immune mechanisms in the pathogenesis of almost all human diseases shown in recent decades, increase in antibiotic resistance and secondary immunodeficiency, aging of the population and widespread use of immunosuppressive drugs and procedures suggest a wider use of immunomodulators in current clinical practice, but the use of most of them limits the lack of knowledge. The most promising compounds for the development as immunomodulating agents and adjuvants for a wide range of vaccines are low molecular weight fragments of peptidoglycan - muramylpeptides. The article describes the mechanisms of action of muramylpeptides, their biological effects and properties of medicines developed on their basis. Special emphasis is placed to glucosaminylmuramyl dipeptide registered in the Russian Federation under the trade name Likopid, which is currently the best - studied drug in its group. The results of Likopid studies when used as a prophylactic and therapeutic agent for infections of various localization in adults and children, for oncological diseases and complications of chemotherapy and radiation therapy, psoriasis, atopic and other diseases are presented. It is emphasized that in diseases associated with human papillomavirus and plaque psoriasis, according to current criteria of evidence - based medicine, Likopid should be classified as drug with level A efficacy (high efficiency in 80-100% of patients). High safety of Likopid in adults and children, including newborns, is noted.

Nonpyrogenic Molecular Adjuvants Based on norAbu-Muramyldipeptide and norAbu-Glucosaminyl Muramyldipeptide: Synthesis, Molecular Mechanisms of Action, and Biological Activities in Vitro and in Vivo.

Fatty acyl analogues of muramyldipeptide (MDP) (abbreviated N-L18 norAbuGMDP, N-B30 norAbuGMDP, norAbuMDP-Lys(L18), norAbuMDP-Lys(B30), norAbuGMDP-Lys(L18), norAbuGMDP-Lys(B30), B30 norAbuMDP, L18 norAbuMDP) are designed and synthesized comprising the normuramyl-l-α-aminobutanoyl (norAbu) structural moiety. All new analogues show depressed pyrogenicity in both free (micellar) state and in liposomal formulations when tested in rabbits in vivo (sc and iv application). New analogues are also shown to be selective activators of NOD2 and NLRP3 (inflammasome) in vitro but not NOD1. Potencies of NOD2 and NLRP3 stimulation are found comparable with free MDP and other positive controls. Analogues are also demonstrated to be effective in stimulating cellular proliferation when the sera from mice are injected sc with individual liposome-loaded analogues, causing proliferation of bone marrow-derived GM-progenitors cells. Importantly, vaccination nanoparticles prepared from metallochelation liposomes, His-tagged antigen rOspA from Borrelia burgdorferi, and lipophilic analogue norAbuMDP-Lys(B30) as adjuvant, are shown to provoke OspA-specific antibody responses with a strong Th1-bias (dominance of IgG2a response). In contrast, the adjuvant effects of Alum or parent MDP show a strong Th2-bias (dominance of IgG1 response).

Eficacia y seguridad de mifamurtida en pacientes com diagnóstico de osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia mapi (metotrexate, doxorrubicina, cisplatino e ifosfamida) / Efficacy and safety of mifamurtide in patients with diagnosis of non-metastatic osteoblastic osteosarcoma without previous systemic treatment, in the context of neoadjuvant chemotherapy with mapi (methotrexate, doxorubicin, cisplatin and ifosfamide)

INTRODUCCIÓN: El presente informe expone la evaluación de tecnología sobre la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia com quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). El osteosarcoma (OS) es un tumor maligno primario del esqueleto y la neoplasia primaria más común del hueso en niños y adultos jóvenes. Representa aproximadamente el 20% de todos los tumores óseos primarios malignos y el 0.2% de todos los tumores malignos. Su curva de distribución en cuanto a la edad es bimodal, con un primer pico en la adolescencia y otro después de los 65 años. La adición de quimioterapia agresiva adyuvante o neoadyuvante a la cirugía há mejorado considerablemente el pronóstico de los pacientes con enfermedad localizada, incrementando la tasa de curación de pacientes con OS en las extremidades y sin enfermedad metastásica evidente de 10-15% a 50-70%. OBJETIVO: El presente dictamen preliminar expone la evaluación de la tecnología sanitaria de la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes com osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). TECNOLOGIA SANITARIA DE INTERES: La mifamurtida (Mepact, Takeda) es un compuesto químico biológicamente activo con actividad inmunomoduladora, clasificándose como un adyuvante biológico y perteneciente al grupo farmacoterapéutico de los inmunoestimulantes (36,37) . El compuesto es un derivado totalmente sintético del muramil dipéptido (MDP), el estimulante inmunológico natural más pequeño de las paredes celulares de micobacterias (37) . Al igual que la MDP, la mifamurtida es reconocida por el receptor de reconocimiento de patrones NOD2, localizado en varios tipos de glóbulos blancos, principalmente monocitos y macrófagos. De tal manera, mifamurtida simula una infección bacteriana, resultando en una activación de los macrófagos y un incremento en la producción de TNF-alfa, interleuquina 1, 6, 8 y 12, y moléculas de adhesión (e.g., ICAM-1 y LFA-1). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del uso de mifamurtida para el tratamiento de pacientes con osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). La búsqueda se realizó utilizando las bases de datos: National Library of Medicine (PubMed, 09/2017), Web of Science (WoS, 09/2017), y Centre for Reviews and Dissemination (CRD, 09/2017). Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como The Cochrane Library (09/2017), The National Institute of Health and Care Excellence (NICE, 08/2017) del Reino Unido, The National Guidelines of Clearinghouse (NGC, 08/2017) de los Estados Unidos, The Scottish Intercollegiate Guidelines Network (SIGN, 08/2017) de Escocia, Australian Clinical Practice Guidelines (08/2017), The Royal Children's Hospital Melbourne Practice Guidelines de Australia (08/2017), CMA Infobase de la Canadian Medical Association (08/2017), American College of Physicians Clinical Practice Guidelines and Recommendations (08/2017) de los Estados Unidos, Guidelines International Network (GIN, 08/2017), New Zealand Guidelines Group (NZGG, 08/2017) de Nueva Zelanda, Guía Salud de España (08/2017, 08/2017), y el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC) de México. Esta búsqueda se completo revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN, 09/2017) de los Estados Unidos, y The European Society for Medical Oncology (ESMO, 08/2017). Por último, se completó la búsqueda ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: se llevó a cabo una búsqueda bibliográfica y de evidencia científica hasta setiembre de 2017 relacionada al uso de mifamurtida en el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). Según las guías consultadas para pacientes con OS no metastásico resecable, referentes al uso de mifamurtida como parte del régimen quimioterapéutico MAPI neoadyuvante (pre-operatorio), no existen recomendaciones generales, unicamente algunas hacen mención al uso de mifamurtida en un contexto de adyuvancia (post-operatorio). El único ensayo clínico que evalúa el uso de mifamurtida dentro del régimen quimioterapéutico MAPI, lo hace en un contexto adyuvante, el cual reporta que no hubo una mejora estadísticamente significativa en relación a la sobreviva libre de eventos (HR 0.78, IC 95%: 0.54 ­ 1.2; p=0.22). Por otro lado, si bien se observó una aparente mejora en relación a la sobrevida global (HR 0.71; IC 95%, 0.52 ­ 0.96, valor p no reportado), es de notar que el límite superior del intervalo de confianza es marginal con respecto al valor nulo de no significancia estadística y que el valor p no ha sido reportado. Asimismo, estos resultados son invalidados por i) interacción observada entre mifamurtida y quimioterapia, afectando el análisis marginal del ensayo, ii) falta de poder estadístico para comparar individualmente los cuatro regímenes quimioterapéuticos evaluados, y iii) aparente falta de poder estadístico para evaluar el efecto de mifamurtida a los regímenes quimioterapéuticos sobre la sobrevida global. Actualmente, no se ha identificado ningún estudio publicado o en proceso dirigido a evaluar los efectos de la mifamurtida neoadyuvante en población con diagnóstico de OS no metastásico. Por lo tanto, no existe evidencia respecto a la eficacia y seguridad de mifamurtida en un contexto pre-operatorio. Se requiere de un ensayo clínico que evalúe la administración de mifamurtida, prévio a la resección del tumor, en la población de interés del presente dictamen. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI no aprueba el uso de mifamurtida para el manejo de los pacientes com diagnóstico de osteosarcoma (OS) osteoblástico no metastásico sin tratamento sistémico en el contexto de neoadyuvancia con quimioterapia MAPI.

[The clinical economic analysis of application of immune correcting preparations to prevent respiratory infections and their complications in frequently ill children of early school age].

The article presents the results of clinical economic analysis of effect of different immune correcting preparations on rate of respiratory infections in 548 frequently ill children of early school age. It is established that preventive immune correction with lysates of bacteria or glucosaminyl muramyl dipeptide in aggregate with vitamin mineral complex results in statistically significant decreasing of rate of respiratory infections and dramatic decreasing of direct and indirect costs of treatment of infectious diseases of respiratory ways. The preventive application of juice of cone-flower herb or interferon in aggregate with vitamnin mineral complex statistically significantly decreases rate of respiratory infections and negligibly decreases direct and indirect costs of their treatment.

Pathomorphosis of experimental infection in mice, infected by Streptococcus pneumoniae, under the effect of immunotropic drugs.

Pathomorphological changes in the organs of animals intranasally infected with Streptococcus pneumoniae were studied under conditions of immunotropic therapy added to antibiotic therapy. The pathomorphosis in the lungs, spleen, and thymus in animals treated with likopid, tinrostim, and roncoleukin was described. A positive time course of the pathological process in experimental animals in comparison with intact animals and animals receiving no immunotropic drugs was demonstrated.

Different effects of the immunomodulatory drug GMDP immobilized onto aminopropyl modified and unmodified mesoporous silica nanoparticles upon peritoneal macrophages of women with endometriosis.

The aim of the present work was to compare in vitro the possibility of application of unmodified silica nanoparticles (UMNPs) and modified by aminopropyl groups silica nanoparticles (AMNPs) for topical delivery of immunomodulatory drug GMDP to the peritoneal macrophages of women with endometriosis. The absence of cytotoxic effect and high cellular uptake was demonstrated for both types of silica nanoparticles. The immobilization of GMDP on the UMNPs led to the suppression of the stimulatory effect of GMDP on the membrane expression of scavenger receptors SR-AI and SR-B, mRNAs expression of NOD2 and RAGE, and synthesis of proteolytic enzyme MMP-9 and its inhibitor TIMP-1. GMDP, immobilized onto AMNPs, enhanced the initially reduced membrane expression of SRs and increased NOD2, RAGE, and MMP-9 mRNAs expression by macrophages. Simultaneously high level of mRNAs expression of factors, preventing undesirable hyperactivation of peritoneal macrophages (SOCS1 and TIMP-1), was observed in macrophages incubated in the presence of GMDP, immobilized onto AMNPs. The effect of AMNPs immobilized GMDP in some cases exceeded the effect of free GMDP. Thus, among the studied types of silica nanoparticles, AMNPs are the most suitable nanoparticles for topical delivery of GMDP to the peritoneal macrophages.

[Use of the immunopotentiator N-acetyl-glucosamine-N-acetylmuramyl dipeptide during triple anti-Helicobacter pylori therapy].

AIM: To evaluate the efficiency of first-line Helicobacter pylori eradication therapy with glucosaminylmuramyldipeptide (Licopid JSC "Peptek", Russia). SUBJECTS AND METHODS: Eradication therapy was performed in 128 patients (84 men and 34 women; mean age 44.1 +/- 13.5 years) with duodenal bulb ulcer associated with H. pylori. The latter was detected in the gastroduodenal mucosa by a morphological study and rapid urease test before and 6-8 weeks after treatment and discontinuation of all drugs. Gastric metaplasia areas in the duodenum were revealed by periodic acid-Schiff and Alcian blue staining. The patients were divided into 4 groups according to the treatment protocol: 1) omeprazole (O) 0.04 g/day, clarithromycin (C) 1 g/day, amoxicillin (A) 2 g/day for 7 days (OCA7; n = 33); 2) the above drugs for 14 days (OCA14; n = 34); 3) O 0.04 g/day, C 1 g/day, A 2.0 g/day for 7 days, and glucosaminylmuramyldipeptide (Licopid) (L) 0.001 g/day for a day (OCA7L1; n = 34) and 4) the above drugs and L 0.01 g/day for 10 (OCA7L10; n = 27). RESULTS: According to the data of intention-to-treat analysis and per protocol, the H. pylori eradication rate was 81.8 and 87.1% for OCA7; 82.4 and 93.3% for OCA14; 88.2 and 93.8% for OCA7L1; 88.9 and 96% for OCA7L10 after PT and RRT, respectively. The rate of side effects was as follows: 6.1% for OCA7; 17.6% for OCA14 (5.9% stopped treatment); 5.9% for OCA7L1; 7.4% for OCA7L10. The cost of the treatment protocols was $ 32 for OCA7; $ 64 for OCA14; $ 40 for OCA7L1; $ 67 for OCA7L10. The intake of glucosaminylmuramyldipeptide (licopid) 0.001 g/day during 7-day triple anti-Helicobacter pylori therapy increased eradication by 6.4% (ITT) and 6.7% (PP), without raising the rate of side effects. CONCLUSION: H. pylori-positive patients with duodenal bulb ulcer should be given glucosaminylmuramyldipeptide (Licopid) 0.001 g/day during 7-day first-line eradication therapy as alternative to the 14-day treatment regimen.

[Methodic approaches to treatment of the chronic generalized parodontitis in elderly and senile patients].

A comprehensive treatment with Likopid of chronic generalized parodontitis in 114 elderly and senile patients was carried out. The state of mechanisms of innate immunity (phagocytosis mechanisms) as well as the profile of proinflammatory cytokines was assessed. The effect of antibiotic-resistant strains of prior microflora on the combined therapy of patients of different age with chronic generalized parodontitis was studied. It is established that due to presence of various types of opportunistic pathogens in patients of different age with parodontitis using the prophylactic antibiotics for the empirical (to determine the antibiotic resistance), a combination of Metronidazole and Lincomycin with the mandatory appointment of immunomodulatory drugs for activation of monocyte-phagocytic system of the patient elderly is most advisable. Use of the drug , "Likopid" significantly improves the results of treatment the elderly and old patients with chronic generalized parodonthitis.

[Experience with use of immunomodulators in treatment of tonsillitis developed at the background of preimmunization by TEOVac].

The use of immunomodulators in the treatment of subjects with postvaccinal reactions to TEOVac was investigated. The most effective schemes were shown to be those with the use of viferon or combination of arbidol and licopide. The terms of the response signs cupping off were much shorter vs. the cases treated with polyoxidonium. The immunomodulating factors did not affect the intensity of the immunity to the vaccine virus.

Single high-dose treatment with glucosaminyl-muramyl dipeptide is ineffective in treating ankylosing spondylitis.

Earlier studies have shown that high doses of TNF-alpha increase apoptosis in human autoimmune T-cell clones. Based on these studies, a treatment approach was proposed to reduce or eliminate autoimmune T cells in patients with type 1 diabetes using drugs that temporarily elevate TNF levels. Here, we report the treatment of ankylosing spondylitis patient with a single high oral dose of Likopid (glucosaminyl-muramyl dipeptide), which aimed at increasing the levels of TNF-alpha in order to induce apoptosis of autoreactive T cells. The flow cytometric analysis of blood samples collected before and after treatment demonstrated massive elimination of CD8(+) T cells. However, the treatment did not result in any notable therapeutic effect, and real-time PCR analysis demonstrated that stably expanded T-cell clones that were earlier tracked in this patient were unaffected. This report suggests that the controversial approach to eliminate autoimmune T-cell clones through overstimulation is not effective in treating ankylosing spondylitis.

[Influence of liposomal glucosaminyl-muramyl dipeptide on superoxide and nitric oxide production by murine macrophages].

Reactive oxygen and nitrogen intermediates are key factors in inflammatory response and antitumoral activity of macrophages. Free and liposomal N-acetylglucosaminyl-N-acetylmuramyl-L-alanyl-D-isoglutamine influence on murine macrophages ability to generate superoxide and nitric oxide were studied. The cells pretreated by GMDP increased superoxide generation in response to secondary stimuli (phorbol ether, lipopolysaccharide, zymosan). Encapsulation in the egg phosphatidylcholine liposomes enhanced cell sensitivity to priming effect of GMDP. The presence of liposomes (up to 0.5 mg/ml) in the medium inhibited superoxide release by macrophages probably due to participation of NO as redox-active metabolite. GMDP (up to 50 microg/ml) alone as well as GMDP with LPS treatment stimulated nitric oxide synthesis by macrophages. Liposomal GMDP at lower concentrations (up to 0.02 microg/ml) enhanced macrophage response to LPS. In contrast, NO-synthetic activity of LPS-stimulated cells decreased along with the increase of liposomal GMDP concentration (up to 0.5 microg/ml). The conditions for effective use of liposomal GMDP in immunotherapy are discussed.

A novel immunostimulator, N-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N6-trans-(m-nitrocinnamoyl)-L-lysine, and its adjuvancy on the hepatitis B surface antigen.

N(2)-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N(6)-trans-(m-nitrocinnamoyl)-L-lysine (muramyl dipeptide C, or MDP-C) has been synthesized as a novel, nonspecific immunomodulator. The present study shows that MDP-C induces strong cytolytic activity by macrophages on P388 leukemia cells and cytotoxic activity by cytotoxic T lymphocytes (CTLs) on P815 mastocytoma cells. Our results also indicate that MDP-C is an effective stimulator for production of interleukin-2 and interleukin-12 by murine bone marrow derived dendritic cells (BMDCs) and production of interferon-gamma by CTLs. Additionally, MDP-C increases the expression levels of several surface molecules, including CD11c, MHC class I, and intercellular adhesion molecule-1 in BMDCs. Moreover, MDP-C remarkably enhances the immune system's responsiveness to hepatitis B surface antigen (HBsAg) in hepatitis B virus transgenic mice for both antibody production and specific HBsAg T-cell responses ex vivo. Our results indicate that MDP-C is an apyrogenic, nonallergenic, and low-toxicity immunostimulator with great potential for diagnostic, immunotherapeutic, and prophylactic applications in diseases such as hepatitis B and cancers.

[Comparison of adjuvant activities of glucosaminyl-muramyl dipeptide and of the gene coding for granulocyte-macrophage colony-stimulating factor in DNA immunization against herpes simplex virus].

Adjuvant activities of granulocyte-macrophage colony-stimulating factor (GM-CSF) and synthetic glucosaminyl-muramyl dipeptide (GMDP) were studied in immunization against type 1 herpes simplex virus (HSV1). Gene encoding the gD HSV1 protein (pDNAgD) was used as an immunogen. Gene encoding GM-CSF in pDNAGM-CSF plasmid, which was developed for eukaryotic expression, and GM-DP were used as immune response modulators. GMDP and plasmid DNA with inserted GM-CSF gene enhanced T-cell immune response to HSV1 after a single injection (pDNAGM-CSF) or 24 h before (GMDP) immunization with the gD HSV1 gene. Both adjuvants increased protective effect of DNA-immunization by a virus gene with 63 up to 100% after injection of two genes and up to 96% after the viral gene was inoculated 24 h after GMDP. These high effects indicate that further investigation of anti-HSV1 DNA-based vaccines used with genetic and peptide adjuvant is prospective.

[New acellular pertussis vaccine, containing glucosaminylmuramyldipeptide]. / Sozdanie novoi beskletochnoi kokliushnoi vaktsiny, vkliuchaiushchei gliukozaminilmuramildipeptid.

As shown in this work, the synthetic immunomodulator glucosaminylmuramyldipeptide (GMDP) can be included into acellular pertussis vaccine (APV). The optimal doses of GMDP, ranging from 0.001 to 0.0001 microg, have been found. These doses enhance the protective activity of APV, especially its low-active doses. GMDP decrease the manifestations of toxic, anaphylactogenic and pyrogenic properties of APV, which may lead to the decrease of the antigenic load of APV on the body of the vaccines and thus to lessening the side-effects of vaccination. GMDP has been shown to considerably increase, in comparison with common pertussis vaccine and APV, the percentage of phagocytizing leukocytes by day 14. The immunization of mice with APV with and without GMDP in doses of 0.01 and 0.001 microg leads to a change in T-lymphocyte/B-lymphocyte ratio in the population of spleen lymphocytes.

Augmentation of NKT and NK cell-mediated cytotoxicity by peptidoglycan monomer linked with zinc.

BACKGROUND: Peptidoglycan monomer (PGM), which was originally prepared by biosynthesis from culture fluids of penicillin-treated Brevibacterium divaricatum, is an immunostimulator, the activities of which might be improved by addition of zinc (Zn) to the basic molecule. METHODS: To test the possible cytotoxic effects of this new analogue, we analyzed the ability of PGM-Zn and PGM to change the phenotypic profile of hepatic and splenic mononuclear lymphatic cells and to affect the growth of malignant T-cell line YAC-1 and syngeneic thymocytes. RESULTS: Pretreatment of C57BL/6 mice primarily with PGM-Zn over 6 days (10/mg/kg intraperitoneally) significantly enhanced the proportions of NK1.1high+, CD4-CD8-, CD69+, and CD3intermediate/NK1.1+/IL2R-beta+ (NKT) cells in the liver, and major histocompatibility complex class II+, CD69+, and CD8+ cells in the spleen. Both types of cells were highly cytotoxic against YAC-1 and syngeneic thymocytes, increasing the destruction of YAC-1 by 70% on addition of hepatic cells and by 30% on addition of splenic cells. Destruction of thymocytes increased by 10 and 50%, respectively. CONCLUSION: The results point to PGM-Zn as a potent cytotoxicity-inducing agent, which also generates autoreactive NKT cells.

[Likopid in the complex immunomodulating treatment of patients with sarcoidosis of the lung and intrathoracic lymph nodes]. / Likopid v kompleksnom immunokorrigiruiushchem lechenii bol'nykh sarkoidozom legkikh i vnutrigrudnykh limfaticheskikh uzlov.

AIM: To examine the functional status of the immune system in patients with lung and intrathoracic lymph nodes sarcoidosis and to evaluate the efficiency of immunomodulation alone and in its inclusion in combined treatment of the disease. MATERIALS AND METHODS: 58 patients with the disease of varying severity were followed up. Comprehensive examination, involving clinical, immunological, X-ray, and physical studies, in patients treated with combined immunotherapy was performed. Initial examination revealed mixed immunodefficiency with impaired T- and phagocytic activity. According to the degree of immunological changes, the patients were given immunotherapy, including polyoxidonium, T-activin (or immunophan) injections, a complex of multivitamins and trace elements, and total adaptogens. After partial or complete normalization of an immunogram, all the patients received licopid (two-three 10-day courses, 10 mg/day). RESULTS: The optimal result (as long as 3-year remission) was achieved in the first time diagnosed sarcoidosis who have not taken glucocorticoidal hormones. CONCLUSION: The follow-up shows that addition of licopid is a compulsory component of immunotherapy in this disease; the efficiency of treatment is determined by its multimodality. The courses of therapy should be repeated when immunological indices deteriorated.

Biologic response modifiers in pediatric cancer.

Biologic response modifiers are becoming an important addition to surgery, chemotherapy, and radiotherapy in the management of cancer. As this field of research grows and expands, more biologic response modifiers will be incorporated into therapeutic regimens. By stimulating the immune system to eradicate minimal residual disease, these agents may improve the disease-free and long-term survival rates of patients with a variety of malignancies. The challenge is to incorporate biologic response modifiers into the treatment armamentarium in ways that will maximize their tumorigenicity.

Immunoprotective properties of peptidoglycan monomer linked with zinc in cholestatic jaundice.

BACKGROUND: Previously it was shown that a new immunostimulator, peptidoglycan monomer linked with zinc (PGM-Zn), might have immunocorrective and hepatotropic effects. Owing to this in the present study we investigated its effects on jaundice-induced immunodysfunction, which might be responsible for serious peri- and postoperative complications in biliary obstruction. METHODS: In vivo effects of PGM-Zn were analyzed in mice subjected to common bile duct ligation (CBDL), where we estimated phenotypic profile and cell cycle of thymocytes, splenocytes and phagocytic function of peritoneal macrophages. In vitro effects of PGM-Zn were evaluated on blastogenesis of human peripheral blood mononuclear cells (PBMNC), obtained from healthy donors and stimulated with anti-CD3 monoclonal antibody and/or PMA, in the presence or absence of jaundice serum obtained from patients with biliary calculosis. RESULTS AND DISCUSSION: Jaundice induced marked disarrangement of lymphatic homeostasis, which at several points might be blocked by PGM-Zn. In mice it delayed the CBDL-induced decline of CD4+ CD8+ thymocytes, decreased the proportion of CD8+ T cells, and increased the percentage of CD4- CD8- thymocytes, augmenting simultaneously the proportion of thymic cells in S and G2 + M phase of cycle. Similar hyperplastic reaction with increased percentage of CD4+, Ig+ and CD5+ cells was noticed in the spleen, together with the enhanced phagocytic ability of peritoneal macrophages. In human PBMNC jaundice reduced the percentages of CD3, CD5, CD4, CD8 and HLA-DR-expressing cells and increased the proportion of CD25 and perforin-positive lymphocytes. PGM-Zn given in vitro was able to abrogate the antiproliferative activity of jaundice serum on PMA and anti-CD3 + PMA-induced blastogenesis.

Study on the reduction of chemotherapy induced neutropenia in mice using glucosaminylmuramyl dipeptide.

Neutropenia is a common and often dose limiting side effect of some chemotherapy regimens. The aim of this study was to investigate the ability of an immunomodulator, glycosaminylmuramyl dipeptide (GMDP, CAS 78113-36-7, romurtide) to reduce chemotherapy induced neutropenia. BALB/c mice were treated with 200 mg kg-1 cyclophosphamide (CY) to induce a reversible neutropenia lasting approximately 6-7 days. There was no change in the duration or depth of neutropenia in mice treated with GMDP for 3 consecutive days (2.5 or 25 mg kg-1) starting the day after CY injection. In addition, at the doses used, the time of administration of GMDP relative to CY did not alter this response. However, a marked neutrophilia compared to controls was consistently observed in all cases. Neutrophil counts of up to 14 times the baseline value were measured 6-7 days after the induction of neutropenia. GMDP had no effect in the absence of CY. Less variation was seen in white cell counts of older non-SPF mice treated with CY. When the activity of GMDP (5 mg kg-1) was compared with G-CSF (granulocyte colony stimulating factor, 100 micrograms kg-1) in these animals, GMDP showed a consistent trend to reduce the length of neutropenia, however, under the conditions tested only G-CSF treatment resulted in a significant reduction in the duration of neutropenia. In the 12-week-old mice, the neutrophilia seen with both G-CSF and GMDP was much smaller than in the 8-week-old mice, and was not significantly different from that in control mice treated with CY alone.