Immunological aspects of liver cell transplantation

Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation(OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation(LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where longterm graft survival is observed on a regular basis and, hence, the liver has been deemed an immuneprivileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.

Suppressive effects of antigens on the activity of specific activated lymphocytes : A test to define the specificity of activated lymphocytes

Objective：With the regular mixed lymphocytes culture （MLC） to detect the allograft rejection, the reactivity of the activated lymphocytes （primed lymphocytes） of a recipient shows sometimes increase and sometimes decrease against the antigens from the donor, which is inconsistent with the clinical results. In order to establish a convenient method for testing the specificity of the activated lymphocytes in vitro, so as to know the rejection occurred or not by testing the existence of the specific activated lymphocytes against donor＇s HLA antigens in the recipient＇s peripheral blood. Methods： Anti-IL-2 neutralizing monoclonal antibody （anti-IL-2 N-mAb） and immunosuppressors were introduced in this test system in the presence of specific stimulators and activated lymphocytes. Results ： When the activated lymphocytes were chosen from the one-way MLC 4 d to undergo re-stimulation by specific stimulators, the activity of activated lymphocytes in the treatment group was suppressed significantly compared with that in the control group. The result of this test method is consistent with the biopsy in the clinical diagnosis of rejection. Conclusion：h suggests that the activated lymphocytes can be inactivated by specific antigens in certain conditions. This can be a useful tool to define the specificity of the activated lymphocytes.

Composite tissue allotransplantation: opportunities and challenges

Vascularized composite allotransplants(VCAs)have unique properties because of diverse tissue components transplanted en mass as a single unit.In addition to surgery,this type of transplant also faces enormous immunological challenges that demand a detailed analysis of all aspects of alloimmune responses,organ preservation,and injury,as well as the immunogenicity of various tissues within the VCA grafts to further improve graft and patient outcomes.Moreover,the side effects of long-term immunosuppression for VCA patients need to be carefully balanced with the potential benefit of a non-life-saving procedure.In this review article,we provide a comprehensive update on limb and face transplantation,with a specific emphasis on the alloimmune responses to VCA,established and novel immunosuppressive treatments,and patient outcomes.

The chemokine receptor CCR7 is a promising target for rheumatoid arthritis therapy

The chemokine receptor CCR7 and its ligands CCL19 and CCL21 guide the homing and positioning of dendritic and T cells in lymphoid organs,thereby contributing to several aspects of adaptive immunity and immune tolerance.In the present study,we investigated the role of CCR7 in the pathogenesis of collagen-induced arthritis(CIA).By using a novel anti-human CCR7 antibody and humanized CCR7 mice,we evaluated CCR7 as a target in this autoimmune model of rheumatoid arthritis(RA).Ccr7-deficient mice were completely resistant to CIA and presented severely impaired antibody responses to collagen II(CII).Selective CCR7 expression on dendritic cells restored arthritis severity and anti-CII antibody titers.Prophylactic and therapeutic treatment of humanized CCR7 mice with anti-human CCR7 mAb 8H3-16A12 led to complete resistance to CIA and halted CIA progression,respectively.Our data demonstrate that CCR7 signaling is essential for the induction of CIA and identify CCR7 as a potential therapeutic target in RA.

Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

The systemic processes involved in the manifestation of life・threatening COVID-19 and in disease recovery are still incompletely understood,despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection.To define hallmarks of severe COVID-19 in acute disease(n=58)and in disease recovery in con valesce nt patie nts(n=28)from Han nover Medical School,we used flow cytometry and proteomics data with unsupervised clustering analyses.In our observational study,we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury.ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies.The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19.Changes within this sign ature were associated with either disease progression or recovery.In summary,our data suggest that besides a strong inflammatory response,severe COVID-19 is driven by endothelial activation and barrier disruption,whereby recovery depends on the regeneration of the endothelial integrity.

Recirculating IL-1R2^(+) Tregs fine-tune intrathymic Treg development under inflammatory conditions

The vast majority of Foxp3^(+)regulatory T cells(Tregs)are generated in the thymus,and several factors,such as cytokines and unique thymic antigen-presenting cells,are known to contribute to the development of these thymus-derived Tregs(tTregs).Here,we report the existence of a specific subset of Foxp3^(+)Tregs within the thymus that is characterized by the expression of IL-1R2,which is a decoy receptor for the inflammatory cytokine IL-1.Detailed flow cytometric analysis of the thymocytes from Foxp3^(hCD2)xRAG1^(GFP) reporter mice revealed that the IL-1R2^(+)Tregs are mainly RAG1^(GFP-)and CCR6^(+)CCR7^(-),demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype.In the spleen,the majority of IL-1R2^(+)Tregs express neuropilin-1(Nrp-1)and Helios,suggesting a thymic origin for these Tregs.Interestingly,among all tissues studied,the highest frequency of IL-1R2^(+)Tregs was observed in the thymus,indicating preferential recruitment of this Treg subset by the thymus.Using fetal thymic organ cultures(FTOCs),we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development resulting in a decreased frequency of CD25^(+)Foxp3^(+)tTregs and an accumulation of CD25^(+)Foxp3^(-)Treg precursors.Interestingly,the addition of IL-1R2^(+)Tregs,but not IL-1R2^(+)Tregs,to reaggregated thymic organ cultures(RTOCs)abrogated the IL-1β-mediated blockade,demonstrating that these recirculating IL-1R2^(+)Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.