Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.

Targeting immunotherapeutics inside the tumor microenvironment (TME) with intact biological activity remains a pressing issue. Mycobacterium indicus pranii (MIP), an approved adjuvant therapy for leprosy has exhibited promising results in clinical trials of lung (NSCLC) and bladder cancer. Whole MIP as well as its cell wall fraction have shown tumor growth suppression and enhanced survival in mice model of melanoma, when administered peritumorally. Clinically, peritumoral delivery remains a procedural limitation. In this study, a tumor targeted delivery system was designed, where chitosan nanoparticles loaded with MIP adjuvants, when administered intravenously showed preferential accumulation within the TME, exploiting the principle of enhanced permeability and retention effect. Bio-distribution studies revealed their highest concentration inside the tumor after 6 h of administration. Interestingly, MIP adjuvant nano-formulations significantly reduced the tumor volume in the treated groups and increased the frequency of activated immune cells inside the TME. For chemoimmunotherapeutics studies, MIP nano-formulation was combined with standard dosage regimen of Paclitaxel. Combined therapy exhibited a further reduction in tumor volume relative to either of the MIP nano formulations. From this study a three-pronged strategy emerged as the underlying mechanism; chitosan and Paclitaxel have shown direct role in tumor cell death and the MIP nano-formulation activates the tumor residing immune cells which ultimately leads to the reduced tumor growth.

A short, 8-week course of imiquimod 5% cream versus podophyllotoxin in the treatment of anogenital warts: A retrospective comparative cohort study.

BACKGROUND: Studies comparing head-to-head treatment modalities for anogenital warts are lacking. AIM: We sought to compare a short, 8-week course of imiquimod 5% cream to versus the standard 4 week course of podophyllotoxin in the treatment of anogenital warts and to assess factors that may affect response to treatment. METHODS: This was a retrospective cohort study. We reviewed medical files of otherwise healthy patients with a first episode of anogenital warts who were treated with either a short, 8-week course of imiquimod or the standard 4-week course of podophyllotoxin. Inverse probability of treatment weighted (IPTW). Logistic regression was employed to evaluate factors that may affect response to therapy. RESULTS: The study included 347 patients. In patients with lesions on dry, keratinized anatomical sites, the complete clearance rates were 7.6% for imiquimod and 27.9% for podophyllotoxin (P < 0.001). In patients with lesions on moist, partially keratinized sites, no difference between the treatments was revealed. Significant predictors of > 50% reduction in wart area were location of lesions [odds ratio (OR) (95% confidence interval (CI)): 3.6 (1.84-7.08), P = 0.0002] for "partially keratinized" versus "keratinized" sites and treatment used [OR (95% CI): 1.79 (1.08-2.97), P = 0.024] for podophyllotoxin versus imiquimod. LIMITATIONS: The retrospective design of the study was a limitation that we mitigated against with the use of IPTW logistic regression. CONCLUSION: A standard 4 week course of Podophyllotoxin was more effective than an 8-week course of imiquimod only for lesions on keratinized sites. Treatment with podophyllotoxin and location of lesions on partially keratinized sites were independent predictors of >50% reduction in wart area.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

Murabutide revisited: a review of its pleiotropic biological effects.

Despite the great efforts put into their development, the list of clinically approved immunological adjuvants is still very short. Evolution of the knowledge of the immune system has enabled for rational design of novel adjuvants and has led to the conclusion that more than one type of adjuvant will be required. Derivatives of muramyl dipeptide (MDP), the minimal immunomodulatory structure of bacterial cell wall peptidoglycan, have gained considerable attention in the past decades, because of their potent adjuvant effects. Murabutide is a safe derivative of MDP, which interacts with cells of the immune system, both innate and adaptive, and exerts its effect through activation of Nod2. The transcriptional response of murabutide-stimulated macrophages revealed enhanced expression of genes coding for various proteins such as immune mediators and their receptors, transcription factors and kinases, ion channels/transporters and proteins involved in cell metabolic activity, thus reflecting a broad spectrum of biological effects. In addition to its well recognized adjuvant effect, murabutide has also been shown to enhance the host's resistance against microbial infections, nonspecific resistance against tumors and the induction of cytokines and chemokines implicated in enhancing the immune response and hematopoesis. This article provides an insight into the mechanism of action of murabutide and its interactions with the cells of the immune system in vitro and in vivo. On account of its numerous biological effects, murabutide has been the subject of several clinical studies. Many of these have confirmed its potential to synergize with cytokines of therapeutic interest in potentiating the tumoricidal activity of macrophages or targeting chronic viral diseases, as well as reducing the cytokine dosage needed to achieve a therapeutic effect. This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases.

Immunotherapeutic efficacy of Mycobacterium indicus pranii in eliciting anti-tumor T cell responses: critical roles of IFNγ.

Mycobacterium indicus pranii (MIP) is approved for use as an adjuvant (Immuvac/Cadi-05) in the treatment of leprosy. In addition, its efficacy is being investigated in clinical trials on patients with tuberculosis and different tumors. To evaluate and delineate the mechanisms by which autoclaved MIP enhances anti-tumor responses, the growth of solid tumors consisting of Sp2/0 (myeloma) and EL4 (thymoma) cells was studied in BALB/c and C57BL/6 mice, respectively. Treatment of mice with a single intra-dermal (i.d.) injection of MIP 3 days after Sp2/0 implantation greatly suppresses tumor growth. MIP treatment of tumor bearing mice lowers Interleukin (IL)6 but increases IL12p70 and IFNγ amounts in sera. Also, increase in CD8(+) T cell mediated lysis of specific tumor targets and production of high amounts of IL2 and IFNγ by CD4(+) T cells upon stimulation with specific tumor antigens in MIP treated mice is observed. Furthermore, MIP is also effective in reducing the growth of EL4 tumors; however, this efficacy is reduced in Ifnγ(-/-) mice. In fact, several MIP mediated anti-tumor responses are greatly abrogated in Ifnγ(-/-) mice: increase in serum Interleukin (IL)12p70 amounts, induction of IL2 and lysis of EL4 targets by splenocytes upon stimulation with specific tumor antigens. Interestingly, tumor-induced increase in serum IL12p70 and IFNγ and reduction in growth of Sp2/0 and EL4 tumors by MIP are not observed in nonobese diabetic severe combined immunodeficiency mice. Overall, our study clearly demonstrates the importance of a functional immune network, in particular endogenous CD4(+) and CD8(+) T cells and IFNγ, in mediating the anti-tumor responses by MIP.

In vitro and in vivo immunostimulatory activity of Woodfordia fruticosa flowers on non-specific immunity.

CONTEXT: Woodfordia fruticosa Kurz. (Lythraceae), a non-rasayana immunomodulatory Indian medicinal plant, used traditionally as an anthelmintic, in dysentery, leprosy, blood diseases, leucorrhea, and menorrhagia. OBJECTIVE: To investigate the effect of ethanol extract of W. fruticosa flowers on non-specific immune responses in mice. MATERIALS AND METHODS: In vitro immunomodulatory activity of the extract was examined on murine peritoneal macrophage phagocytosis (nitroblue tetrazolium (NBT) dye reduction, lysosomal enzyme activity, nitric oxide and myeloperoxidase) and on proliferation of bone marrow cells by sulforhodamine B (SRB) assay, while the in vivo potential on macrophages and bone marrow cells was evaluated by using carbon clearance test and cyclophosphamide-induced myelosuppression, respectively. RESULTS: Significant increase in the release of myeloperoxidase, nitric oxide lysosomal enzyme and superoxide from macrophages along with significant increase in phagocytic index in carbon clearance test indicate stimulatory activity of the extract on macrophages. The extract also demonstrated 60% increase in bone marrow cell proliferation and offer protection towards cyclophosphamide-induced myelosuppression which represents the stimulation of bone marrow activity. DISCUSSION: Significant increase in mediators released from macrophages and phagocytic index in carbon clearance test suggests the release of cytokines from macrophages and stimulation of reticulo-endothelial system. Proliferation of bone marrow cells indicates the plausible release of colony stimulating factors, which further stimulates the immune system through generation of immune cells. CONCLUSION: The result described here indicates the immunostimulatory activity of ethanol extract of W. fruticosa flowers by stimulating non-specific immune responses, macrophages and bone marrow cells.

Effectiveness of BCG vaccination among leprosy contacts: a cohort study.

The study assessed the effectiveness of BCG vaccination against leprosy among the contacts of 1161 leprosy patients at the FIOCRUZ Leprosy Outpatient Clinic, RJ, Brazil, from June 1987 to December 2006. Following National Leprosy Program guidelines, the clinic has administered one-to-two doses to all healthy contacts since 1991. Among the 5680 contacts, 304 (5.4%) already had leprosy. Of the 5376 eligible healthy contacts, 3536 were vaccinated, 30 of whom were excluded due to previous or current tuberculosis, or HIV. In 18 years of follow up, 122 (2.15%) incident cases were diagnosed (58 vaccinated and 64 not), 28 occurring in the first year of follow up (21 vaccinated, 16 with no scar). The protection conferred by BCG was 56% and was not substantially affected by previous BCG vaccination (50% with a scar and 59% without). The risk of tuberculoid leprosy during the initial months was high among those vaccinated with no scar. However, it had substantially declined by the first year and in the following years, when the protection rate in this group reached 80%. Since Brazil is endemic for leprosy and the detection rate is not declining satisfactorily, vaccinating all contacts could be an effective means of substantially reducing the incidence of leprosy.

New vaccines against tuberculosis: lessons learned from BCG immunisation in Brazil.

The current tuberculosis (TB) vaccine Mycobacterium bovis BCG has been employed for some 70 years in Brazil and lessons from its use should be taken in account for the development or improvement of new TB vaccines. The vast majority of the current population has been vaccinated with BCG, with the possible requirement for a booster immunisation in adulthood for TB protection. BCG Moreau strain also protects against leprosy, meningitis and extrapulmonary forms of TB. Factors related to differences in strain, dosage and BCG administering protocol have been responsible for the variable efficacy of BCG. This vaccine is clearly affected by, as yet unclear, host and/or environmental variables. In this brief review, we describe some aspects of BCG immunisation observed in Brazil that may be of importance for improving or replacing BCG.

Talidomida y análogos de talidomida / Thalidomide and analogous

La talidomida se introdujo en la década del '50 como droga hipnótica, sedante y antiemética, especialmente indicada en mujeres gestantes durante el primer trimestre del embarazo. Se asociaron al uso del fármaco graves anormalidades congénitas y polineuropatías, por lo que se la retiró del mercadoen los años '60. Posteriormente se comprobaron propiedades inmunomoduladoras en pacientes con eritema nudoso lepromatoso, así como también efectos antiinflamatorios como lupus eritematoso discoide, enfermedad de Behcet, úlceras aftosas en pacientes con SIDA, enfermedad crónica injerto contra huésped, mieloma múltiple y neoplasia de órganos sólidos. Actualmente, con el desarrollo de nuevos fármacos análogos de la talidomida, que conservan sus propiedades terapéuticas sin presentar teratogenicidad, su aplicación futura es más promisoria

Talidomida y análogos de talidomida / Thalidomide and analogous

La talidomida se introdujo en la década del 50 como droga hipnótica, sedante y antiemética, especialmente indicada en mujeres gestantes durante el primer trimestre del embarazo. Se asociaron al uso del fármaco graves anormalidades congénitas y polineuropatías, por lo que se la retiró del mercadoen los años 60. Posteriormente se comprobaron propiedades inmunomoduladoras en pacientes con eritema nudoso lepromatoso, así como también efectos antiinflamatorios como lupus eritematoso discoide, enfermedad de Behcet, úlceras aftosas en pacientes con SIDA, enfermedad crónica injerto contra huésped, mieloma múltiple y neoplasia de órganos sólidos. Actualmente, con el desarrollo de nuevos fármacos análogos de la talidomida, que conservan sus propiedades terapéuticas sin presentar teratogenicidad, su aplicación futura es más promisoria (AU)

Thalidomide as a novel therapeutic agent: new uses for an old product.

Thalidomide and its immunomodulatory analogues have numerous effects on the body's immune system, including potential anti-cancer and anti-inflammatory activities. Thalidomide is currently used experimentally to treat various cancers, dermatological, neurological and inflammatory diseases. This drug is approved in the USA for cutaneous manifestations of lepromatous leprosy and is in Phase III trials for multiple myeloma. Thalidomide and its analogues modulate the immune system in various ways. Some of these immunomodulatory activities, together with the anti-angiogenic, anti-proliferative and pro-apoptotic properties, are believed to mediate anti-tumor responses as observed in multiple myeloma and some solid tumors. The analogue lenalidomide has shown potential in treating the bone marrow disorders multiple myeloma and myelodysplastic syndrome, and is presently in Phase II and III trials, respectively.

Levamisole in dermatology : a review.

Levamisole, an anthelmintic agent with a wide range of immunomodulatory actions, has been used successfully as monotherapy and an adjunct to treatment in a variety of diseases. Since 1990, combination therapy of levamisole and fluorouracil has played an important role in the treatment of resected Dukes stage C adenocarcinoma of the colon. Because of its immunomodulating effects levamisole has been used in a wide range of diseases with and without success. In dermatologic disease levamisole has been successfully used in the treatment of parasitic, viral and bacterial infections including leprosy, collagen vascular diseases, inflammatory skin diseases and children with impaired immune a variety of reasons. It has also been used in combination with other drugs for treating a number of dermatologic disorders, e.g. in combination with cimetidine for treating recalcitrant warts, with prednisolone for treating lichen planus, erythema multiforme and aphthous ulcers of the mouth. Adverse affects of levamisole are mild and infrequent and include rash, nausea, abdominal cramps, taste alteration, alopecia, arthralgia, and a flu-like syndrome. It can rarely cause agranulocytosis. More studies need to be undertaken to study the full potential of levamisole in dermatologic diseases.

Thalidomide: an old drug with new clinical applications.

Thalidomide has several targets and mechanisms of action: a hypnosedative effect, several immunomodulatory properties with an effect on the production of TNF-alpha and the balance between the different lymphocyte subsets and an antiangiogenic action. Thalidomide has been used in several cutaneous inflammatory disorders (e.g., erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus and severe aphtosis), cancers (e.g., relapsed/refractory multiple myeloma, malignant melanoma and systemic signs in cancer) and inflammatory conditions (e.g., Crohn's disease and rheumatoid arthritis). Several side effects are associated with thalidomide. Some are major, such as teratogenicity, peripheral neuropathy and deep vein thrombosis. Somnolence and rash are frequently reported when thalidomide is used at higher doses as an anticarcinogenic agent and can lead to dose reduction or treatment discontinuation depending on severity. Minor side effects include abdominal pain and endocrine disturbances. To prevent the teratogenicity, use of thalidomide is strictly controlled in western countries with close adherence to a birth control programme. Close monitoring for early development of peripheral neuropathy is also recommended.