Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury.

Disturbance of single-cell transcriptional heterogeneity is an inevitable consequence of persistent donor-specific antibody (DSA) production and allosensitization. However, identifying and efficiently clearing allospecific antibody repertoires to restore single-cell transcriptional profiles remain challenging. Here, inspired by the high affinity of natural bacterial proteins for antibodies, a genetic engineered membrane-coated nanoparticle termed as DSA trapper by the engineering chimeric gene of protein A/G with phosphatidylserine ligands for macrophage phagocytosis was reported. It has been shown that DSA trappers adsorbed alloreactive antibodies with high saturation and activated the heterophagic clearance of antibody complexes, alleviating IgG deposition and complement activation. Remarkably, DSA trappers increased the endothelial protective lineages by 8.39-fold, reversed the highly biased cytotoxicity, and promoted the proliferative profiles of Treg cells, directly providing an obligate immune tolerant niche for single-cell heterogeneity restoration. In the mice of allogeneic transplantation, the DSA trapper spared endothelial from inflammatory degenerative rosette, improved the glomerular filtration rate, and prolonged the survival of allogeneic mice from 23.6 to 78.3 days. In general, by identifying the lineage characteristics of rejection-related antibodies, the chimeric engineered DSA trapper realized immunoadsorption and further phagocytosis of alloantibody complexes to restore the single-cell genetic architecture of the allograft, offering a promising prospect for the treatment of alloantibody-mediated immune injury.

Corrigendum: Lymphatic reconstruction in kidney allograft aggravates chronic rejection by promoting alloantigen presentation.

[This corrects the article DOI: 10.3389/fimmu.2021.796260.].

Lymphatic Reconstruction in Kidney Allograft Aggravates Chronic Rejection by Promoting Alloantigen Presentation.

Chronic rejection of the renal allograft remains a major cause of graft loss. Here, we demonstrated that the remodeling of lymphatic vessels (LVs) after their broken during transplantation contributes to the antigen presenting and lymph nodes activating. Our studies observed a rebuilt of interrupted lymph draining one week after mouse kidney transplantation, involving preexisting lymphatic endothelial cells (LECs) from both the donor and recipient. These expanding LVs also release C-C chemokine ligand 21 (CCL21) and recruit CCR7+ cells, mainly dendritic cells (DCs), toward lymph nodes and spleen, evoking the adaptive response. This rejection could be relieved by LYVE-1 specific LVs knockout or CCR7 migration inhibition in mouse model. Moreover, in retrospective analysis, posttransplant patients exhibiting higher area density of LVs presented with lower eGFR, severe serum creatinine and proteinuria, and greater interstitial fibrosis. These results reveal a rebuilt pathway for alloantigen trafficking and lymphocytes activation, providing strategies to alleviate chronic transplantation rejection.

Comparison of Graft Outcome Between Donation After Circulatory Death and Living-Donor Kidney Transplantation.

BACKGROUND: Donation after cardiac death (DCD) and living-donor (LD) kidney transplantation are the main kidney transplantation types in China. But the outcome of DCD kidney transplantation compared with LD kidney transplantation remains unclear. METHODS: In this study, 325 DCD and 409 LD kidney transplantations were included. We retrospectively compared 3-year graft survival, death-censored graft survival, recipient survival, and graft function. All kidneys of the DCD group were procured from voluntary donation after the citizens' death by the Organ Procurement Organization (OPO) in the presence of the Red Cross, and the transplantation application was approved by the Organ Transplant Ethics Committee. RESULTS: The graft function at year 3 in the DCD group was superior to that of the LD group (eGFR: 71.14±22.28 vs 64.29±16.76 mL/min/1.73 m2; P < .001). After matching donor age, there was no significant difference between the paired DCD and LD group (eGFR: 62.22±18.50 vs 66.99±17.81 mL/min/1.73 m2; P = .068). The 3-year graft survival (94.7% vs 97.4%; P = .041) and recipient survival (97.2% vs 99.5%; P = .011) were a little worse in the total DCD group. However, once the DCD kidney transplantation recipients survived more than 2 months, graft and recipient survival rates were similar between the DCD and LD groups (97.7% vs 97.4%, P = .866 and 99.5% vs 99.0%, P = .466). These results were confirmed in an age-paired groups study. Severe infection was the main cause of graft loss and recipient death in the early stage of DCD transplantation. CONCLUSIONS: Medium- and long-term graft function of DCD kidney transplantation were comparable to LD kidney transplantation. Our results supported the continued use of DCD kidneys.

[Early conversion from calcineurin inhibitor to sirolimusto after renal transplantation:a prospective, open-label and non-randomized control study].

OBJECTIVE: To explore the efficacy and safety of designed early conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) as major immunosuppressive therapy in renal transplant recipients with stable renal function. METHODS: A prospective, open-label and non-randomized control study was performed for 112 renal transplant recipients (3-6 months post-operation) with stable renal function between June 2008 and June 2011. The patients in SRL group (n = 57) switched to sirolimus while those in CNI group (n = 55) continued CNI. The dosing of mycophenolate mofetil and steroids had no change. They were followed up for at least 24 months to evaluate the acute rejection, patient and graft survival, renal function, estimated glomerular filtration rate (eGFR), blood lipids, blood glucose, liver function and urinary protein at 1, 6, 12 and 24 months after inclusion. Adverse events were also recorded. RESULTS: The serum creatinine of SRL group decreased significantly after conversion ( (89.2 ± 24.7), (87.6 ± 23.8), (86.1 ± 20.4), (86.7 ± 19.7) vs (117.0 ± 16.3) µmol/L, all P < 0.05). CNI group showed no improvement of renal function.SRL group had a significantly higher eGFR than CNI group (P < 0.05). Among 3 cases of acute rejection, there were 2 in SRL group and 1 in CNI group (P > 0.05). Blood lipids in SRL group increased significantly at 1 month after conversion (P < 0.05) and reverted back to average level after intervention (P > 0.05).SRL group had a drop of hemoglobin level within the normal range. Two patients in SRL group developed hypokalemia and another 2 patients had oral ulcer. They all improved after treatment. During follow-ups, 1 case of mild proteinuria was found in SIR group. Three patients were diagnosed with diabetes (1 in SRL group vs 2 in CNI group). CONCLUSIONS: Early conversion from CNI to SRL as major immunosuppressive therapy in renal transplant recipients with stable renal function further improves renal function. There is no higher rate of acute rejection during follow-up.Elevated blood lipids after conversion may be easily controlled. No other adverse events are found.