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Results for “immunomodulation”

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PubMed1992

Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator Linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia.

Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.

Adjuvants, Immunologic↗

PubMed1995

Downregulation of intragraft IFN-gamma expression correlates with increased IgG1 alloantibody response following intrathymic immunomodulation of sensitized rat recipients.

A single intrathymic injection of donor-specific spleen cells (2 x 10(7)) abrogates accelerated (24 hr) rejection of LBNF1 cardiac allografts in presensitized LEW rats and prolongs graft survival to about 11 days. This effect is donor-specific, gamma-irradiation-sensitive, thymus-dependent, and requires no concomitant therapy. We have recently shown that following intrathymic alloantigen administration, there is an earlier and increased systemic production of alloreactive IgM, and subsequently a premature isotype switching to IgG with the predominant IgG1 and IgG2a alloantibody responses. There is also a preferential binding of these IgG subclasses to the endothelium of well-functioning allografts. In this work, we analyzed the early cell activation and related cytokine elaboration patterns at the mRNA and protein levels by competitive template RT-PCR and immunohistochemistry, respectively. We found that prolonged cardiac allograft survival following intrathymic administration of donor spleen cells in presensitized rats was associated with markedly depressed intragraft IFN gamma mRNA and protein expression. Moreover, intrathymic allostimulation has led to a defect in the IL-2 pathway as the expression of IL-2 and IL-2R protein at the graft site was inhibited despite stable IL-2 mRNA levels. The inhibition of cell activation was also demonstrated by reduced MHC class II and the lack of ICAM-1, and TNF-alpha expression by immunohistochemistry. The expression of biologically active IL-12 (p70) by mononuclear and endothelial cells was detected in rejecting grafts between 3 and 12 hr. The well-functioning grafts after intrathymic allostimulation were devoid of IL-12 (p70), which in turn may have contributed to the downregulation of IFN-gamma mRNA and protein. Treatment with r.IFN-gamma, but not with r.IL-2, recreated the rejection response, and the characteristic IgG subclass pattern associated with accelerated graft loss. Hence, intrathymic immunomodulation with alloantigen results in selective inhibition of IFN-gamma-producing cells and a preferential upregulation of IgG1 alloantibodies. These data support the notion of the interlocked immunoregulatory roles of cytokine and alloantibody networks in rat allograft recipients.

Animals↗

PubMed2002

Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD.

BACKGROUND: FTY720 is a novel immunomodulator with a unique mechanism of action, i.e. chemokine-dependent lymphocyte homing into secondary lymphoid organs associated with profound lymphocyte depletion in blood. We investigated its efficacy, either FTY720 alone or together with cyclosporine or the rapamycin derivative rapamycin derivative (RAD), in cynomolgus monkey kidney allotransplantation. METHODS: Life-supporting allotransplantation was performed in bilaterally nephrectomized hosts. Compounds were given once daily by oral gavage. Monitoring was done by serum creatinine and urea, and rejection was concluded when values exceeded 500 micromol/L and 50 mmol/L, respectively (5-6 times the upper limit of reference values). Rejection was confirmed by graft histology. The termination point was set to 100 days after transplantation. In addition, animals were monitored for 24 hr drug concentrations and thorough inspection of potential adverse side effects. RESULTS: FTY720 given alone at 3.0 mg/kg per day prolonged rejection-free survival (33-85 days, mean 24 hr concentration between 54 and 66 ng/mL [n=3]), but it was not efficacious at a 0.3 mg/kg per day dose. For cyclosporine alone, 30 mg/kg per day during maintenance was efficacious (average concentration above 100 ng/mL, historical data from our group), and for RAD alone 0.75 mg/kg per day (concentration above 10 ng/mL). Efficacious FTY720-cyclosporine-A (CsA) or FTY720-RAD combinations were established using 0.1-0.3 mg/kg per day FTY720, 10-30 mg/kg per day cyclosporine, and/or 0.25-0.50 mg/kg per day RAD. Compared with single-compound treatment, FTY720 effective doses and 24 hr trough concentrations were at least tenfold lower in combination treatment and those of cyclosporine and RAD about twofold lower, indicative of effective synergy between the compounds. Already at the lowest FTY720 dose tested (0.03 mg/kg per day), there was a profound lymphocyte depletion down to about 30% of pretransplant values, which further increased at the highest dose (3.0 mg/kg per day, to about 14% of pretransplant values). Lymphocyte depletion was reflected by a decrease in T and B subpopulations. CONCLUSION: FTY720 is an effective immunosuppressant in prevention of acute kidney allograft rejection in cynomolgus monkeys and synergizes with cyclosporine and/or RAD in yielding rejection-free allograft survival.

Administration, Oral↗

PubMed2003

Recent advances in immunomodulation in the treatment of inflammatory bowel disease.

This review in depth considers the thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine, methotrexate, ciclosporin, infliximab and less well-established immunomodulators (including thalidomide, mycophenolate, tacrolimus and natalizumab among others) in their role of modifying the course of ulcerative colitis and Crohn's disease. The five papers are preceded by an overview on the therapeutic order of precedence, the indications and duration of therapy, as well as future concepts.

Colitis, Ulcerative↗

PubMed2005

Immunomodulating and anti-apoptotic action of ursodeoxycholic acid: where are we and where should we go?

Ursodeoxycholic acid (UDCA) is currently used in clinical practice worldwide not only for the dissolution of cholesterol gallstones, but also, mainly, to treat patients with chronic cholestatic liver diseases. However, the mechanisms of action of UDCA at the hepatocyte and cholangiolyte levels are still not completely understood. Much progress has been made from the first concept that the only mechanism of action of this bile acid was its choleretic action. One of the most fascinating mechanisms of action that was evoked for UDCA is its immunomodulating and anti-apoptotic action, which could, in part, be explained by its interaction with the glucocorticoid nuclear receptor at the hepatocyte level. Glucocorticoids, whose prototype is dexamethasone, are the major ligands of the glucocorticoid receptor. The biological effects of glucocorticoids are driven by a multiple-step reaction including binding of the steroid to the glucocorticoid receptor, DNA binding, receptor transformation, nuclear translocation and either positive or negative gene transactivation. In this issue of the journal, Weitzel and co-workers clearly demonstrated that the binding of UDCA to the glucocorticoid receptor is unspecific. Therefore, the anti-inflammatory, cytoprotective and anti-apoptotic actions of UDCA should be due not only to the mild interaction with the glucocorticoid receptor, but also to transactivation or transrepression of different cytoplasmic proteins that are involved in the survival pathway.

Animals↗

PubMed2005

Refractory coeliac disease: remission with infliximab and immunomodulators.

Coeliac disease is a T-cell-mediated enteropathy induced by gluten. A minority of patients who fail to respond to a gluten-free diet may require intervention with immunomodulating drugs. We report a case of refractory coeliac disease where remission was induced by the anti-tumour necrosis factor-alpha antibody infliximab and was maintained with prednisolone and azathioprine.

Aged↗

PubMedDate not supplied

Immunomodulation and blood transfusion.

Over the past three decades, evidence from a variety of sources has suggested that allogeneic blood transfusions can induce clinically significant immunosuppression in recipients. This clinical syndrome is referred to in the transfusion medicine literature as transfusion-associated immunomodulation (TRIM) and has been linked to an improved clinical outcome in the setting of renal transplantation. Possible deleterious TRIM-associated effects include increased prevalence of cancer recurrence and postoperative bacterial infections. The recognition that TRIM can increase morbidity and mortality in allogeneically transfused individuals has become a major concern for those involved in transfusion medicine. Whether TRIM predisposes recipients to increased risk for cancer recurrence and/or bacterial infections is still not proven, however. In contrast to the available clinical data, studies in experimental animal models suggest that TRIM is an immunologically mediated biologic effect associated with the infusion of allogeneic leukocytes, which can be ameliorated by prestorage leukoreduction. Although considerable data have been accumulated in an attempt to unravel the clinically adverse effects of TRIM, the precise mechanism of TRIM has yet to be elucidated. Further studies, both basic and applied, to establish the clinically relevant manifestations of TRIM as well as the mechanism(s) are urgently required.

Adjuvants, Immunologic↗

PubMed2005

Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acid-induced experimental colitis.

Inflammatory bowel diseases are characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and antiinflammatory reactivity. In an attempt to downregulate inflammatory bowel disease, we tested whether the immunomodulator glatiramer acetate (GA; Copaxone, copolymer 1), an approved drug for the treatment of multiple sclerosis, can ameliorate trinitrobenzene sulfonic acid (TNBS)-induced colitis, a murine model that resembles human Crohn's disease. Experimental colitis was induced by rectal instillation of TNBS in 3 mice strains: BALB/c, SJL/J, and (SJL/JXBALB/c)F1, and its severity was evaluated by gross colon injury, histologic damage, body weight, and survival rate. We studied the effect of GA on all these parameters as well as on lymphocyte reactivity manifested by proliferation and secretion of tumor necrosis factor-alpha, and transforming growth factor-beta. GA treatment significantly suppressed the various manifestations of TNBS-induced colitis as demonstrated by substantial reduction in the macroscopic colonic damage, preservation of the microscopic colonic structure, reduced weight loss, and improved long-term survival, in GA treated mice compared with untreated mice. The parenteral route was more effective than the oral route. GA suppressed the proliferation of local mesenteric lymphocytes to syngeneic colon extract and the detrimental tumor necrosis factor-alpha secretion. In addition, it induced a beneficial secretion of transforming growth factor-beta. The ability of GA to effectively modulate the clinical manifestations and the detrimental immune response involved in experimental colitis warrants further studies to determine the clinical efficacy of GA in the treatment of human inflammatory bowel diseases.

Animals↗

PubMed2002

Clinical tolerance and immunologic effects after single or repeated administrations of the synthetic immunomodulator murabutide in HIV-1-infected patients.

Correction of the virus-induced deficits in innate immunity of HIV-infected subjects could well contribute to enhanced immune recovery and efficacious control of viral replication. The safe synthetic immunomodulator Murabutide (ISTAC Biotechnology, Lille, France) has been found to regulate the function of antigen-presenting cells and to selectively activate CD4 lymphocytes leading to dramatic suppression of HIV replication, in vitro. Therefore, as a first step toward the evaluation of the immunotherapeutic potential of Murabutide in HIV disease, we have conducted two phase 1/2 clinical trials to address the safety and the immunologic effects of Murabutide administration into HIV-infected subjects receiving antiretroviral therapy. The first study revealed that single administration of 5, 7, or 9 mg of Murabutide, to 6 patients per dose, was well tolerated. This was accompanied by a selective induction of cytokines and chemokines detectable in the serum, and the levels appeared to plateau at the 7-mg dose. The second study then evaluated the safety and biological effects of repeated administrations of 7 mg Murabutide, on 5 consecutive days, in 12 HIV-1-infected patients. A good clinical tolerance was noted throughout the study. Moreover, changes in several immune parameters, including downregulation of coreceptor expression on lymphocytes and improved lymphoproliferative responses, were detected during or/and up to 3 weeks after Murabutide administration. These encouraging results warrant further evaluation of longer periods or cycles of immunotherapy with Murabutide in HIV-infected subjects.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2004

Immunomodulation: the future of allergy and asthma treatment.

PURPOSE OF REVIEW: As the prevalence of asthma and allergic disease increases around the world, it is clear that more effective therapies and disease-modifying agents are needed. Treatment for allergic disease is evolving with an increase in understanding of the etiology. RECENT FINDINGS: The first immunomodulatory treatment was recently approved for use in the United States when the Food and Drug Administration approved the use of a humanized monoclonal anti-IgE antibody in patients with allergic asthma. Another strategy that has proved effective in a murine model is the downregulation of the whole immune system by targeting adhesion molecules, which has been evaluated in a recent human trial. Other strategies for the treatment of allergic diseases concentrate on refocusing the immune system away from an allergic-type response. These include the use of targeted therapies towards specific cytokines, cytokine receptors or chemokine receptors, and the use of specific bacterial DNA sequences (unmethylated cytosine-guanine dinucleotides). Finally, attention is being focused on possible therapies that may tilt the immune response to a non-allergic response by interfering with signaling molecule pathways. SUMMARY: Immunomodulation will play a key role in future therapies for allergic disease. These treatment modalities may not only treat allergic disease, but also be beneficial in reducing the morbidity and mortality for which it is responsible.

Animals↗

PubMed2004

Genetically engineered negative signaling molecules in the immunomodulation of allergic diseases.

PURPOSE OF REVIEW: This review summarizes current knowledge regarding the control of human mast cell and basophil signaling and recent developments using a new therapeutic platform consisting of a human bifunctional gamma and epsilon heavy chain (Fc gamma-Fc epsilon) protein to inhibit allergic reactivity. RECENT FINDINGS: Crosslinking of Fc gamma RIIb to Fc epsilon RI on human mast cells and basophils by a genetically engineered Fc gamma-Fc epsilon protein (GE2) leads to the inhibition of mediator release upon Fc epsilon RI challenge. GE2 protein was shown to inhibit cord blood-derived mast cell and peripheral blood basophil mediator release in vitro in a dose-dependent fashion, including inhibition of human IgE reactivity to cat. IgE-driven mediator release from lung tissue was also inhibited by GE2. The mechanism of inhibition in mast cells included alterations in IgE-mediated Ca mobilization, spleen tyrosine kinase phosphorylation and the formation of downstream of kinase-growth factor receptor-bound protein 2-SH2 domain-containing inositol 5-phosphatase (dok-grb2-SHIP) complexes. Proallergic effects of Langerhan's like dendritic cells and B-cell IgE switching were also inhibited by GE2. In vivo, GE2 was shown to block passive cutaneous anaphylaxis driven by human IgE in mice expressing the human Fc epsilon RI and inhibit skin test reactivity to dust mite antigen in a dose-dependent manner in rhesus monkeys. SUMMARY: The balance between positive and negative signaling controls mast cell and basophil reactivity, which is critical in the expression of human allergic diseases. This approach using a human Fc gamma-Fc epsilon fusion protein to co-aggregate Fc epsilon RI with the Fc gamma RII holds promise as a new therapeutic platform for the immunomodulation of allergic diseases and potentially other mast cell/basophil-dependent disease states.

Animals↗

PubMed2006

Immunomodulation of allergic responses by targeting costimulatory molecules.

PURPOSE OF REVIEW: This review focuses on putative targets, including costimulatory and additional pathways involving T regulatory cells, that may be critical for modifying allergic responses. RECENT FINDINGS: Multiple costimulatory signals including CD28/CTLA4: CD80/CD86, ICOS: ICOSL, OX40:OX40L and PD-1: PD-L1/PD-L2 have been identified and implicated in the regulation of immune disorders. Recent studies indicate that T regulatory cells may also suppress T cell costimulation by the secretion of TGF-beta and IL-10, suggesting an important role of T regulatory cells in the regulation of allergic disorders. SUMMARY: Immune-mediated disorders, including allergic diseases, have been increasing in prevalence. Unravelling these immune pathways may suggest new targets for immunomodulation.

Animals↗

PubMed2006

Pneumonia as a complication of blood product transfusion in the critically ill: transfusion-related immunomodulation (TRIM).

BACKGROUND: An increased risk of postoperative infection (including pneumonia) attributable to the receipt of allogeneic blood transfusion has been investigated as a possible manifestation of transfusion-related immunomodulation (TRIM) in 16 randomized controlled trials (RCTs) and approximately 40 observational studies. OBJECTIVES: This review categorizes RCTs and observational studies with regard to the inference that they permit about possible mediators of TRIM-allogeneic white cells (WBCs), WBC-derived soluble mediators, and/or allogeneic plasma-and examines whether the totality of the clinical evidence supports an association between allogeneic blood transfusion and postoperative infection. RESULTS: When all available studies are considered together in meta-analyses, three types of studies show no increased risk of postoperative infection in association with allogeneic blood transfusion: a) RCTs comparing recipients of buffy-coat-reduced and prestorage-filtered, WBC-reduced allogeneic red cells; b) RCTs comparing recipients of allogeneic and autologous blood; and c) observational studies comparing patients transfused before and after implementation of WBC reduction. RCTs comparing recipients of nonbuffy-coat-reduced and WBC-reduced red blood cells may point to a TRIM effect, but they cannot yet be subjected to formal meta-analysis. CONCLUSIONS: No overwhelming clinical evidence has been presented to establish the existence of a TRIM effect that relates allogeneic blood transfusion to postoperative infection.

Blood Transfusion, Autologous↗

PubMed2003

Immunomodulators and aromatase inhibitors: are they the next generation of treatment for endometriosis?

PURPOSE OF REVIEW: This article will present an overview of current and new hormonal and non-hormonal medical treatment in the management of endometriosis, with special emphasis on immunomodulators and aromatase inhibitors. RECENT FINDINGS: Recent research shows a very promising role for new hormonal medication (aromatase inhibitors, estrogen and progesterone receptor modulators) and anti-inflammatory drugs (tumor necrosis factor-alpha inhibitors, matrix metalloproteinase inhibitors, cyclooxygenase-2 inhibitors) in the management of endometriosis. SUMMARY: The ideal drug in the treatment of endometriosis alleviates pain and cures sub-fertility without inhibition of ovulation or menstruation and without significant side effects or teratological effects. Such a drug would allow conception during treatment and would fundamentally change the management of endometriosis from a surgical approach to medical management. Although such a drug does not yet exist, promising research using tumor necrosis factor inhibitors indicates that this could become possible in the not too distant future. We strongly recommend testing new medication for the prevention or treatment of endometriosis in the baboon model, an established research model for fundamental and preclinical research in endometriosis.

Adjuvants, Immunologic↗

PubMed2006

Oleuropein: a novel immunomodulator conferring prolonged survival in experimental sepsis by Pseudomonas aeruginosa.

Oleuropein, a novel immunomodulator derived from olive tree, was assessed in vitro and in experimental sepsis by Pseudomonas aeruginosa. After addition in monocyte and neutrophil cultures, malondialdehyde, TNF-alpha, IL-6, and bacterial counts were estimated in supernatants. Acute pyelonephritis was induced in 70 rabbits after inoculation of pathogen in the renal pelvis. Intravenous therapy was administered in four groups postchallenge by one multidrug-resistant isolate (A, controls; B, oleuropein; C, amikacin; D, both agents) and in three groups postchallenge by one susceptible isolate (E, controls; F, oleuropein; G, amikacin). Survival was recorded; bacterial growth in blood and organs was counted; endotoxins (LPS), malondialdehyde, total antioxidant status, and TNF-alpha in serum were estimated. TNF-alpha and IL-6 of cell supernatants were not increased compared with controls when triggered by LPS and P. aeruginosa. Counts of multidrug-resistant P. aeruginosa were decreased in monocyte supernatants. Median survival of groups A, B, C, D, E, F, and G were 3.00, 6.00, 2.00, 10.00, 1.00, 5.00, and 1.00 days, respectively. Bacteria in blood were lower at 48 h in groups B and D compared with A and in groups F and G compared with E. Total antioxidant status decreased steadily over time in groups A, C, D, and G, but not in groups B and F. TNF-alpha of groups B, C, and D was lower than A at 48 h. Tissue bacteria decreased in group F compared with E. Oleuropein prolonged survival in experimental sepsis probably by promoting phagocytosis or inhibiting biosynthesis of proinflammatory cytokines.

Amikacin↗

PubMed2005

Tolerance to rat heart grafts induced by intrathymic immunomodulation is mediated by indirect recognition primed CD4+CD25+ Treg cells.

BACKGROUND: In a rat model (PVG.R8-to-PVG.1U) disparate for one class I antigen, RT.1Aa, we previously demonstrated that intrathymic immunomodulation with donor antigens resulted in prolonged survival of cardiac allografts that underwent chronic rejection. However, long-term survivors developed a regulatory cell population that prevented both acute and chronic rejection when adoptively transferred into secondary graft recipients. The purpose of this study was to characterize these regulatory cells with particular emphasis on CD4+CD25+ Treg cells. METHODS: Spleens, lymph nodes, and peripheral blood lymphocytes of secondary tolerant recipients were characterized using antibodies to various T cell markers in flow cytometry. In vitro MLR and in vivo adoptive transfer experiments were conducted to investigate the involvement of CD4+CD25+ T cells in the observed tolerance. The presence of various cytokines in the sera of graft recipients and MLR culture supernatants was tested using ELISA. RESULTS: Tolerant recipients compared with naive rats had substantially higher percentages of CD4+CD25+ T cells in the spleen (28+/-3% vs. 11+/-5%) and blood (23+/-6% vs. 9+/-4%). Tolerant animals also had higher levels of serum IL-10 than naive and rejecting animals. CD4+CD25+ T cells from secondary long-term graft survivors inhibited donor-specific proliferative responses in vitro that was associated with high IL-10 production. Importantly, depletion of CD4+CD25+ T cells from splenocytes of tolerant rats abrogated their ability to transfer tolerance to tertiary graft recipients. CONCLUSIONS: Our data demonstrate that cardiac allograft tolerance in this model is mediated by CD4+CD25+ Treg cells primed by indirect recognition and is associated with high levels of IL-10.

Adoptive Transfer↗

PubMed1985

Immunomodulation by myxospores of Myxococcus xanthus.

Glycerol-induced myxospores of Myxococcus xanthus caused non-specific modulation of humoral and cellular immune responses in laboratory animals. The number of cells which formed specific haemolysins in spleens of mice immunized with sheep erythrocytes was increased when 0.5 X 10(8) myxospores were inoculated 2 d after the erythrocytes, and decreased when myxospores were injected 2 d before or at the same time as the erythrocytes. Both the IgG primary response and the secondary response to erythrocytes were decreased in rabbits after pretreatment with 2 X 10(8) myxospores per rabbit. Delayed-type hypersensitivity to sheep erythrocytes was also suppressed in mice after intraperitoneal (i.p.) injection of 0.3 X 10(8) myxospores. One day after i.p. injection of myxospores, neither an inflammatory response nor bone marrow cell depletion was observed in mice. These results support the idea that M. xanthus myxospores possess diverse immunomodulation properties apparently due to factors different from the classical LPS of Gram-negative bacteria.

Animals↗

PubMed1993

The effects of RU 41.740, a glycoprotein immunomodulating agent derived from Klebsiella pneumoniae, on intra-abdominal abscess formation in mice.

The prophylactic and therapeutic efficacies of the immunomodulating agent RU 41.740 (a glycoprotein extract from Klebsiella pneumoniae) were studied in a murine model of intra-abdominal abscess formation with Bacteroides fragilis, Escherichia coli, and bran as an abscess-potentiating agent. Parenteral injection of RU 41.740, either before or after injection of an abscess-inducing mixture (AIM), was associated with significantly diminished incidence and size of abscesses. Abscess incidence and size were significantly decreased by oral administration of RU 41.740 after, but not before, AIM injection. Abscess formation and resolution are the results of complex interactions of host defence mechanisms with bacteria and potentiating agent, and RU 41.740 has been shown previously to activate both macrophage and neutrophil function. These results indicate that activation of non-specific defences may protect against abscess development in chronic sepsis.

Abdomen↗