R. Deng

Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells.

TCR specific antibodies may modulate the TCR engagement with antigen–MHC complexes, and in turn regulate in vivo T cell responses to alloantigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57–597), TCRα or CD3 promptly reduced the number of CD4+ and CD8+ T cells in normal mice, but H57–597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57–597 mAb, the expansion of SEB‐reactive Vβ8+ T cells was completely abrogated while SEB‐nonreactive Vβ2+ T cells remained unaffected. More importantly, transient H57–597 mAb treatment exerted long‐lasting effect in preventing T cell responses to alloantigens, and produced long‐term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor‐specific long‐term graft survival, T cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57–597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin‐sensitized recipients. Thus, transient modulation of the TCRβ chain by H57–597 mAb exhibits potent, long‐lasting therapeutic effects to control alloimmune responses.

Novel Sphingosine-1-Phosphate Receptor Modulator KRP203 Combined With Locally Delivered Regulatory T Cells Induces Permanent Acceptance of Pancreatic Islet Allografts

Background KRP203, a structural FTY720 analogue, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1) versus S1PR3 and 100-fold greater selectivity over S1PR2 and S1PR5. Although the immunoregulatory effects of FTY720 have been tested in clinical and experimental research, the therapeutic efficacy of KRP203 in allograft models remains elusive. In this study, we investigated the potential of KRP203 alone and in combination with intragraft injection of CD4+CD25+FoxP3+ regulatory T cells (Tregs) to induce islet allograft tolerance. Methods BALB/c (H-2d) mice received transplants of fresh C57BL/10 (H-2b) islet allografts under the kidney capsule and were treated for 7 days with 0.3, 1.0, or 3.0 mg/kg KRP203 alone or in combination with intragraft-infused Tregs. Results Untreated BALB/c mice acutely rejected C57BL/10 islet allografts at a mean survival time of 13.8±2.7 days (n=5). A 7-day dosing of 0.3 or 1.0 mg/kg KRP203 produced long-term islet allograft survival (>200 days) in one of five and two of seven recipients, respectively. A 3 mg/kg KRP203 dose resulted in islet graft survival for more than 200 days in 5 of 12 recipients. Whereas recipients that received 500 allogeneic islets admixed with 5×105–7×105 Tregs survived 83.6±67.2 days, addition of transient 3 mg/kg KRP203 therapy induced prolonged drug-free graft survival (>200 days) in all recipients. Conclusions A brief treatment with KRP203 significantly prolonged islet allograft survival, whereas additional intragraft delivery of Tregs induced tolerogenic effects selective to islet alloantigens.

En bloc kidney transplantation from infant donors younger than 10 months into pediatric recipients

Early graft loss and poor graft function limit the use of kidneys from infant donors. Six en bloc kidney transplantations were performed from infant donors younger than 10 months into pediatric recipients between November 2012 and September 2015 at our center. We retrospectively analyzed recipient and donor demographics, surgery procedures, complications, graft function and size, and patient and graft survival with a follow‐up of 6‐39 months (median 15.5 months). Donor age ranged from 1 to 10 months with weight ranging from 3.5 to 10 kg. Recipient age ranged from 10 to 16 years with weight ranging from 30 to 39 kg. One kidney was removed due to arterial thrombosis during surgery, while the other kidney of this en bloc graft remained viable. Urine leak followed by bilateral ureteral obstruction occurred in one recipient. All of the recipients showed immediate graft function. The size of the en bloc kidney increased from 4.2±0.6 cm to 7.6±0.6 cm 6 months after surgery. Patient and graft survival were both 100% at the last follow‐up. Our results show that en bloc kidney transplantation from infant donors younger than 10 months into pediatric recipients is effective under the condition of experienced surgical techniques and perioperative management.

Anti-TCR mAb induces peripheral tolerance to alloantigens and delays islet allograft rejection in autoimmune diabetic NOD mice.

Background Clinical application of islet transplantation to treat type 1 diabetes has been limited by islet allograft destruction by both allogeneic and autoimmune diabetogenic T-cell responses. The current study aims at determining whether an anti–T-cell receptor (TCR) monoclonal antibody (mAb) has potential as a novel and potent induction immunotherapy for islet transplantation. Methods We have investigated the therapeutic efficacy and mechanisms of action of anti-TCR therapy in four different murine models, which comprise either allo- or autoimmune responses alone or both together. Results T-cell response to islet allografts was potently abrogated by a brief treatment with an anti-TCR&bgr; mAb (clone H57-597), resulting in long-term survival of BALB/c islet allografts in streptozotocin-induced diabetic B6 mice. Moreover, transient anti-TCR treatment permanently prevented BALB/c skin allograft rejection on Rag1−/− B6 recipients that were reconstituted with Foxp3+ cell–depleted B6 splenocytes, but did not impair the reconstituted cells’ ability to reject the later transplanted C3H skin allografts (transplanted at 120 days after BALB/c skin grafting). Transient anti-TCR treatment was also able to completely prevent diabetes onset in NOD.SCID.&ggr;c−/− mice that were transferred with lymphocytes from diabetic NOD mice. Next, transient anti-TCR treatment significantly prolonged the survival of transplanted BALB/c islets in overtly diabetic NOD mice, which comprise both allogeneic and autoimmune diabetogenic T-cell responses to the transplanted islets. Conclusions Overall, anti-TCR mAb induced peripheral tolerance to specific alloantigens even in the absence of Foxp3-expressing natural regulatory T cells. These findings reveal the potential for using TCR-targeting mAbs as induction immunotherapy for islet transplantation.

Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen−1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.

Dendritic Cells Transduced with Single Immunoglobulin IL-1-Related Receptor Exhibit Immature Properties and Prolong Islet Allograft Survival

Members of toll-like receptor-interleukin 1 receptor signaling [TLR/IL-1R (TIR)] superfamily mediate maturation of dendritic cells (DCs) and launch immune response in transplanted organs. In this study, we hypothesized that TIR8, also known as single immunoglobulin IL-1-related receptor (SIGIRR) molecule, refrain DCs from maturation and induce immune tolerance of transplanted organ. DCs were transduced with the recombinant adenovirus Ad5F35 to highly express SIGIRR (DC-SIGIRR), then injected to murine recipient before islet transplantation. It revealed that DCs transduced with SIGIRR had low expression of major histocompatibility and costimulatory molecules along with strong phagocytic ability in vitro assay. The data demonstrated that recipients treated with DC-SIGIRR had satisfying islet allograft function and long survival times, with an increase of Treg and reduction of Th17 in both spleen and draining lymph nodes in vivo. Therefore, genetic modification of SIGIRR inhibits DC activation and maturation, affects differentiation of T cell subsets, protects allograft biological function, and prolongs graft survival.

The efficacy and safety of intensified enteric‐coated mycophenolate sodium with low exposure of calcineurin inhibitors in Chinese de novo kidney transplant recipients: a prospective study

The aim of this study was to investigate the efficacy and safety of a transient intensified enteric‐coated mycophenolate sodium (EC‐MPS) dosing regimen with low exposure of calcineurin inhibitors (CNIs) in Chinese de novo kidney transplantation.

Effect of Early Immunosuppression Therapy on De Novo Anti–Human-Leukocyte-Antigen Antibody After Kidney Transplantation

The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production.nnnMETHODSnA single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and Februaryxa02016.nnnRESULTSnA total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242).nnnCONCLUSIONnThe risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects.

Higher Renal Allograft Function in Deceased-Donor Kidney Transplantation Rather Than in Living-Related Kidney Transplantation

OBJECTIVESnTo compare the clinical outcome of kidney transplantation from living-related and deceased donors.nnnPATIENTS AND METHODSnConsecutive adult kidney transplants from living-related or deceased donors from February 2004 to December 2015 in a single center were enrolled for retrospective analysis. Estimated glomerular filtration rate (eGFR) was compared with linear mixed models controlling the effect of repeated measurement at different time points.nnnRESULTSnThere were 536 living-related and 524 deceased donor kidney transplants enrolled. The 1-year, 3-year, and 5-year graft survival rates were 98.8%, 98.5% and 97.2% in living-related kidney transplantation (KTx), and 94.9%, 91.3% and 91.3% in deceased donor KTx (log-rank, Pxa0< .001). A significantly higher incidence of delayed graft function (DGF) was observed in deceased donor KTx (20.6% vs 2.6%, Pxa0< .001). eGFR in deceased donor KTx was significantly higher than that in living-related KTx (68.0 ± 23.7 vs 64.7 ± 17.9 mL/min/1.73 m2 at 1 year postoperation, 70.1 ± 23.3 vs 64.3 ± 19.3 mL/min/1.73 m2 at 2 years postoperation, and 72.5 ± 26.2 vs 65.2 ± 20.4 mL/min/1.73 m2 at 3 years postoperation; Pxa0< .001). The donor age was significantly higher in living-related KTx group (47.5 ± 11.0 vs 31.1 ± 14.4 years, Pxa0< .001).nnnCONCLUSIONnLiving-related graft survival is superior to deceased graft survival at this center, while better 5-year renal allograft function is obtained in deceased donor KTx patients, which may be attributable to the higher age of living-related donors.

The early outcomes of candidates with portopulmonary hypertension after liver transplantation

BackgroundPortopulmonary hypertension (PPH) was once regarded as a contraindicaton to liver transplantation (LT). However, growing evidence has indicated that PPH patients undergoing LT may show similar outcomes compared to those without PPH, and researchers have recommended it not be an absolute contraindication. Given this controversy, we aimed to identify and review the current evidence on this topic and to provide a comparison of the outcomes after LT between candidates with PPH and those without.MethodsWe systematically searched the MEDLINE, EMBASE and Cochrane Library databases for all studies that compared the outcomes of PPH patients and those without PPH after LT. All studies reporting outcomes of PPH patients versus those without PPH (Control) were further considered for inclusion in this meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between PPH and Control groups.ResultsEleven retrospective trials and one prospective, randomized, controlled trial, involving 37,686 transplant recipients were included. The PPH patients had increased 1-year mortality with an OR of 1.59 (95% CIu2009=u20091.26–2.01, Pu2009=u20090.0001) compared to the control group. There was no significant difference in graft loss and 30-day mortality after LT between the two groups.ConclusionsPatients with PPH who underwent LT had increased 1-year mortality compared to those without PPH, while graft loss and 30-day mortality were similar. Nevertheless, LT may be a reasonable therapeutic option for some patients with PPH, but further studies are needed to identify those select patients with PPH who would benefit most from LT.