Analysis of alloreactivity and intragraft cytokine profiles in living donor liver transplant recipients with graft acceptance
Mitsuhisa TakatsukiShinji UemotoYukihiro InomataSeisuke SakamotoMichihiro HayashiMikiko UedaTakashi KanematsuKoichi Tanaka
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Immunosuppression
Mixed lymphocyte reaction
Post-transplant immunosuppression almost always includes a combination of drugs and approaches based on a patient's individual situation, organ transplanted, and current developments in the field. Depending on these factors, approaches could include Induction immunosuppression, Maintenance immunosuppression, or Anti-rejection immunosuppression.
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For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope.Parents of children with LT completed an internet-based survey about their child's immunosuppression.Children of respondents (n = 82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4 vs. >4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p < .005).Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.
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Regimen
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Immunosuppression
Liver disease
Orthotopic liver transplantation
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Subsets of T cells, defined by the patterns of cytokines that they secrete, show important functional differences, and appear to be at least partly responsible for the different immune responses induced by various pathogens. Two very distinct subsets, TH1 and TH2, are mutually inhibitory, and a newly discovered cytokine, ILI0, is one of the mediators of this cross-regulation. IL10 inhibits the synthesis of cytokines by TH1 cells but not TH2 cells. Since TH2 cells produce IL4 and IL5, which lead to some of the major manifestations of allergy, it is likely that IL10 production biases an immune response towards allergy.
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Splenocyte
Interleukin 15
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Codonopsis lanceolatae have been used as one of the traditional remedies as well as food source. We previously reported that in vitro supplementation of Codonopsis lanceolatae water extracts enhanced the splenocytes proliferation compared to the control group. This study, the combined immunomodulative effect of water extract Codonopsis lanceolatae was Seven to eight weeks old mice(balb/c) was fed ad libitum on chow diet and water extract of Codonopsis lanceolatae was orally administrated every other day for four weeks at two different concentrations(50 and 500 mg/kg B.W.). The production of cytokine(IL-2, IL-10 and IFN-), secreted by macrophages stimulated with LPS or not, were detected by ELISA assay using the cytokine kit. The result of ex vivo study showed that the IL-2, IL-10 and IFN- was detected at 500 mg/kg B.W. supplementation group with LPS stimulation in all cases. Also, ratio of IFN-, IL-10 was the range of 37 with mitogen stimulation such as Con A and LPS. In conclusion, this study suggests that Codonopsis lanceolatae extracts may enhance the immune function by regulating the cytokine(IL-2, IL-10 and IFN-) prodution capacity by activated macrophages in mice.
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Interleukin 3
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Acute and chronic liver diseases are dynamic processes causing numerous physiological and metabolic derangements. There are many supportive treatments for end-stage liver disease but the only definitive treatment is liver transplantation and the current effectiveness of liver transplantation, to a large extent, can be attributed to improvements in immunosuppression. This chapter describes a brief history of immunosuppression in liver transplantation, the rationale for immunosuppression, commonly used immunosuppression medications, common immunosuppressive regimens and unique circumstances that may require tailoring of medications. We also provide a brief introduction to future agents on the horizon.
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Liver disease
Orthotopic liver transplantation
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Costimulation of murine macrophages with immune complexes (ICs) and TLR ligands leads to alternative activation. Studies on human myeloid cells, however, indicate that ICs induce an increased pro-inflammatory cytokine production. This study aimed to clarify the effect of ICs on the pro- versus anti-inflammatory profile of human polarized macrophages.Monocytes isolated from peripheral blood of healthy donors were polarized for four days with IFN-γ, IL-4, IL-10, GM-CSF, M-CSF, or LPS, in the presence or absence of heat aggregated gamma-globulins (HAGGs). Phenotypic polarization markers were measured by flow cytometry. Polarized macrophages were stimulated with HAGGs or immobilized IgG alone or in combination with TLR ligands. TNF, IL-6, IL-10, IL-12, and IL-23 were measured by Luminex and/or RT-qPCR.HAGGs did not modulate the phenotypic polarization and the cytokine production of macrophages. However, HAGGs significantly altered the TLR-induced cytokine production of all polarized macrophage subsets, with the exception of MΦ(IL-4). In particular, HAGGs consistently enhanced the TLR-induced IL-10 production in both classically and alternatively polarized macrophages (M1 and M2). The effect of HAGGs on TNF and IL-6 production was less pronounced and depended on the polarization status, while IL-23p19 and IL-12p35 expression was not affected. In contrast with HAGGs, immobilized IgG induced a strong upregulation of not only IL-10, but also TNF and IL-6.HAGGs alone do not alter the phenotype and cytokine production of in vitro polarized human macrophages. In combination with TLR-ligands, however, HAGGs but not immobilized IgG shift the cytokine production of distinct macrophage subsets toward IL-10.
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A member of the costimulatory molecule family, inducible costimulator (ICOS), is expressed on activated T cells and plays a critical role in their primary activation and cytokine production. ICOS is involved in different immune phenomena, such as Th1-mediated autoimmune disease and graft rejection. Although blockade of ICOS costimulation theoretically may protect grafts from rejection, a single dose of anti-ICOS antibody did not result in the prolongation of rat liver allograft survival. However, in this article, we report that anti-rat ICOS antibody markedly enhanced the immunosuppressive activity of a suboptimal dose of tacrolimus (FK506). After fully allogenic DA to LEW liver transplantation, recipients received a single injection of tacrolimus (1 mg/kg, intramuscularly) with or without anti-ICOS antibody (1 mg/kg, intravenously). Recipient survival was significantly prolonged in rats treated with both the antibody and suboptimal tacrolimus (median survival time 44 days vs. 28 days with tacrolimus alone, P < .01). The extent of cell infiltration into the graft was closely associated with prolongation of recipient survival. Our findings thus demonstrate that anti-ICOS antibody immunotherapy combined with suboptimal tacrolimus has a synergistic effect in preventing hepatic allograft rejection and that it may induce long-term graft acceptance intimately associated with a marked reduction of intragraft T lymphocyte infiltration. (Liver Transpl 2004;10:743–747.)
Immunosuppression
Donor-Specific Antibodies
Graft rejection
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