Belatacept, an investigational selective costimulation blocker, did not appear to be inferior to cyclosporine as a means of preventing acute rejection after renal transplantation. Belatacept may preserve the glomerular filtration rate and reduce the rate of chronic allograft nephropathy.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day

There are no studies which have compared the risk of severe Covid‐19 and related mortality between transplant recipients and non‐transplant patients. We enrolled two groups of patients hospitalized for Covid‐19, i.e., kidney transplant recipients from the French Registry of Solid Organ Transplant (n=306) and a single‐center cohort of non‐transplant patients (n=795). An analysis was performed among subgroups matched for age and risk factors for severe Covid‐19 or mortality. Severe Covid‐19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death.Transplant recipients were younger and had more comorbidities compared to non‐transplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30‐day cumulative incidence of severe Covid‐19 did not differ between KTR and non‐transplant patients; however, 30‐day Covid‐19‐related mortality was significantly higher in KTR (17.9% versus 11.4%, respectively, p=0.038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C‐reactive protein (CRP) were associated with severe Covid‐19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR=1.55), and creatinine level >115 µmol/L (HR=2.32) were associated with Covid‐19‐related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. Kidney transplant recipients had a higher Covid‐19‐related mortality compared to non‐transplant hospitalized patients.

The soluble HLA-G5 isoform encoded by intron-4 retaining spliced transcript has been previously detected in vivo in sera and grafts from transplanted patients who had significantly better graft acceptance. These findings led us to investigate the role of HLA-G5 in tolerance induction in vitro and its biological relevance in allograft acceptance in vivo. We demonstrated that engagement of Ig-like transcript-2 and Ig-like transcript-4 receptors by HLA-G5 is involved in inhibition of T cell alloproliferative responses. Naive T cells sensitized in vitro with HLA-G5, for as little as 18 h, 1) lost their ability to respond to subsequent allogeneic stimulus, and 2) acquired regulatory properties because they inhibited the reactivity of other T cells. These HLA-G5-induced T cells act in an Ag-nonspecific fashion and through soluble factors. Biological relevance was provided by ex vivo analyzes of samples from liver-kidney cotransplanted patients who had high HLA-G5 serum levels and no graft rejection. We showed that addition of HLA-G5-containing sera from these patients inhibited T cell alloresponses and that serum HLA-G5 was responsible for this inhibition. Notably, PBMC from transplanted patients exposed to high levels of circulating HLA-G5 did not respond to allostimulation and inhibited alloreactivity of other T cells. These results demonstrate that HLA-G5-mediated tolerance involves the induction of immunosuppressive T cells. These findings provide evidence supporting the tolerogenic properties of HLA-G and emphasize its potential application as a relevant therapeutic candidate capable of limiting allograft rejection.

IntroductionMesenchymal stem cells (MSCs) are important tools in treating immune disorders and in tissue repair by their multipotency, immunosuppressive properties, and production of cytokines or growth factors, Many sources of MSCs have been described and the main candidates for clinical application are bone marrow and adipocyte tissues widely available and easy to collect by standardized procedures. However, as they have in vitro and in vivo time-limited functions, 1,2 several research groups are searching for MSCs with prolonged lifetime and immunoregulatory properties. In the last decade, MSCs have been isolated from fetal or neonatal tissues [3][4][5][6][7] and embryonic tissues (ES-MSCs). [8][9][10] At present, no specific markers for the origin of the MSCs have been identified and all types of MSCs are defined by their CD105, CD90, CD73, CD44, CD29, CD146, and CD166 expression. Adult BM-MSCs exhibit immunomodulatory functions on immune cells by both cell-cell contact and soluble factors. 2,[11][12][13] Recently, human somatic cells have been successfully reprogrammed into induced pluripotent cells (iPSC) [14][15][16][17][18][19] that exhibit characteristics similar to human ES. 20 IPSC hold enormous promise for personalized cellreplacement therapy 21 and for research into various human diseases. 22,23 Therefore, MSCs derived from iPSC may be a novel source of tolerance induction, though their immunosuppressive activity remains to be explored.We report that MSCs isolated from diverse human iPS Cell lines (iPS-MSCs) can strongly inhibit the cytotoxic functions of natural killer (NK) cells. Most of these MSC-mediated inhibitory effects are because of a general impairment of NK activation and disruption of the secretory machinery on NK cells. Interestingly, iPS-MSCs and ES-MSCs are more resistant than BM-MSCs to preactivated NK cells. Our current data indicate that iPS-MSCs could represent a promising alternative strategy for the treatment of various immune-mediated diseases. Methods ReagentsThe antibodies used to assess NK and MSC phenotypes are described in supplemental Table 1 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Recombinant human IL-2 was purchased from Immunotools, whereas Mitomycin, Monensin, and Brefaldin were purchased from Sigma-Aldrich. 1-Methyl-tryptophan (1-MT) and NS-398, specific inhibitors for Indoleamine 2,3-dioxygenase (IDO) and Prostaglandin (PGE)-2, respectively, were also purchased from Sigma-Aldrich. 87G antagonist antibody anti-HLA-G was purchased from Exbio. Pluripotent stem-cell linesWe used 3 human iPS cell lines PB3, PB10, and PB11 provided from the Stem cell Core-Facility (ES Team Paris Sud, University Paris 11, Villejuif, France) that were derived from amniotic fluid cells (AFC-iPS) after amniocentesis (Antoine Béclère Hospital, Clamart France). Their pluripotency was validated by teratoma assay, flow cytometry and RT-PCR and registered into the European Registry Web site (http://www.hescreg.eu). In addition, we de...

HLA-G is