The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).

Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond.

Antibody mediated rejection (ABMR) in the kidney can show a wide range of clinical presentations and histopathologic patterns. The Banff 2019 classification currently recognizes four diagnostic categories: 1. Active ABMR, 2. Chronic active ABMR, 3. Chronic (inactive) ABMR, and 4. C4d staining without evidence of rejection. This categorization is limited in that it does not adequately represent the spectrum of antibody associated injury in allograft, it is based on biopsy findings without incorporating clinical features (e.g., time post-transplant, de novo versus preformed DSA, protocol versus indication biopsy, complement inhibitor drugs), the scoring is not adequately reproducible, and the terminology is confusing. These limitations are particularly relevant in patients undergoing desensitization or positive crossmatch kidney transplantation. In this article, I discuss Banff criteria for these ABMR categories, with a focus on patients with pre-transplant DSA, and offer a framework for considering the continuum of allograft injury associated with donor specific antibody in these patients.

Paving the Way Towards Universal Chimeric Antigen Receptor Therapy in Cancer Treatment: Current Landscape and Progress.

Chimeric antigen receptor (CAR) therapy has been proved effective in a stream of clinical trials, especially in hematologic malignancies. However, current CAR therapy is highly personalized as cells used are derived from patients themselves, which can be costly, time-consuming, and sometimes fails to achieve optimal therapeutic results due to poor quality/quantity of patient-derived cells. On the contrary, universal CAR therapy, which is based on healthy individuals' cells, circumvents several limitations of current autologous CAR therapy. To achieve the universality of CAR therapy, the allogeneic cell transplantation related issues, such as graft-versus-host disease (GVHD) and host-versus-graft activities (HVGA), must be addressed. In this review, we focus on current progress regarding GVHD and HVGA in the universal CAR therapy, followed by a universal CAR design that may be applied to allogeneic cells and a summary of key clinical trials in this field. This review may provide valuable insights into the future design of universal CAR products.

[Indications and management of hematologic microtransplantation: Recommendations of the French Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)]. / Atelier d'harmonisations 2019 : indications et organisation d'une microtransplantation de cellules souches hématopoïétiques.

Microtransplantation (MT) is based on injection of HLA-mismatched G-CSF mobilized hematopoietic stem cells, in combination with chemotherapy but without use of conditioning regimen nor immunosuppressive drugs. As a result, a transient microchimerism is induced without engraftment. Its efficacy relies both on host immune system stimulation (recipient versus tumor) and on a graft versus tumor effect. Data are scarce and concern mostly Asian patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (HR-MDS). In comparison to conventional treatment without MT, higher complete remission rates and longer disease free survival and overall survival have been reported. Safety seems acceptable. The most frequent adverse event is non-severe cytokine release syndrome. Risk of GVHD remains very low. Here, we summarize the published data and detail the practical aspects of the procedure. Current data are not strong enough to provide recommendations on indications. Nevertheless, it seems reasonable to propose MT to patients with AML or HR-MDS, regardless of age, presenting an indication for allogeneic stem cell transplantation but ineligible for it. MT is still under investigation and rather be proposed within clinical trials.

Novel Engraftment and T Cell Differentiation of Human Hematopoietic Cells in ART-/-IL2RG-/Y SCID Pigs.

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. In this work we have generated T- B- NK- SCID pigs through site directed CRISPR/Cas9 mutagenesis of IL2RG within a naturally occurring DCLRE1C (ARTEMIS)-/- genetic background. We confirmed ART-/-IL2RG-/Y pigs lacked T, B, and NK cells in both peripheral blood and lymphoid tissues. Additionally, we successfully performed a bone marrow transplant on one ART-/-IL2RG-/Y male SCID pig with bone marrow from a complete swine leukocyte antigen (SLA) matched donor without conditioning to reconstitute porcine T and NK cells. Next, we performed in utero injections of cultured human CD34+ selected cord blood cells into the fetal ART-/-IL2RG-/Y SCID pigs. At birth, human CD45+ CD3ε+ cells were detected in cord and peripheral blood of in utero injected SCID piglets. Human leukocytes were also detected within the bone marrow, spleen, liver, thymus, and mesenteric lymph nodes of these animals. Taken together, we describe critical steps forwards the development of an immunologically humanized SCID pig model.

Evaluación de formulaciones inmunoterapéuticas experimentales en el modelo hibrido murino de Reaccion del Injerto contra el Hospedador / Evaluation of experimental immunotherapeutic formulations in the hybrid murine model of Graft-versus-Host Reaction

Introducción: La Enfermedad del Injerto Contra el Hospedador es la complicación más frecuente de los Trasplantes de Células Madre Hematopoyéticas y de todos los trasplantes que contengan células inmunocompetentes alogénicas, el 100 por ciento la padecen y cerca del 30 por ciento mueren por su causa; una proporción alta de casos son esteroide-refractarios, asimismo otras medidas inmunosupresoras modernas fracasan. En los campos de la Inmunoterapia y la Vaccinología también existe una escasez preocupante de inmunomoduladores de origen biológico potentes, efectivos, seguros y de amplio espectro. Existe un modelo híbrido murino de gran utilidad metodológica para estudios experimentales. Objetivo: Evaluar dos formulaciones novedosas de origen biotecnológico, una de ellas inmunopotenciadora y otra inmunosupresora, desarrolladas como cocleatos. Material y Métodos: Mediante Microscopia Electrónica y RT-PCR se caracterizaron las formulaciones como nanopartículas y su capacidad de regular la expresión del ARNm de linfoquinas definitorias de sus perfiles, respectivamente. Empleando el modelo de Enfermedad del Injerto Contra el Hospedador en ratón híbrido F1 (CBAxC57BL), se evaluó su carácter inmunomodulador in vivo . Resultados: Partiendo de los proteoliposomas de Neisseria meningitidis, se obtuvieron dos formulaciones en forma de cocleatos, ambas con diámetros de partícula inferior a 100nm. La Formulación 1mostró un perfil proinflamatorio con potente capacidad de aumentar el IFNγ y el TNFα y potenció el Índice de Bazo hasta 2,05 en el modelo EICH con p=0,0002. La Formulación 2 mostró un perfil supresor-regulatorio con potente capacidad de aumentar la IL-10 y el TGFβ y además de suprimir la producción de TNFα. En el modelo usado, esta formulación, suprimió el Índice de Bazo de manera dosis dependiente y con alta significación estadística. Se corroboró el conocido perfil de seguridad y ausencia de reactogenicidad de ambas formulaciones. Conclusiones: Ambas formulaciones tienen potencial aplicación en los campos de la terapia de Enfermedad del Injerto Contra el Hospedador en otras patologías y en Vaccinología. Los resultados obtenidos en el presente trabajo fundamentan la conveniencia de continuar el desarrollo farmacéutico y completar la preclínica de ambas formulaciones(AU)

Introduction: Graft-versus-host disease is the most frequent complication of Hematopoietic Stem Cell Transplants and all transplants containing allogeneic immunocompetent cells; 100 percent of patients suffer from this complication and about 30 percent die for this particular cause. A high proportion of cases are steroid-refractory; likewise, other modern immunosuppressive measures fail. In the fields of Immunotherapy and Vaccinology, there is also a worrying shortage of powerful, effective, safe and broad spectrum immunomodulators of biological origin. There is a hybrid murine model of great methodological utility for experimental studies. Objective: To evaluate two novel formulations of biotechnological origin: an immunopotentiator formulation and an immunosuppressive one, which were developed as cochleates. Material and Methods: The formulations assayed by Electron Microscopy and RT-PCR were characterized as nanoparticles and for their capacity to regulate lymphokine mRNA expression profile, respectively. The immunomodulatory character was evaluated in vivo using Graft-versus-host disease in (CBAxC57BL) F1 hybrid mice. Results: Starting from the proteoliposomes derived from Neisseria meningitides, two cochleate formulations were obtained, both with particle diameters below 100 nm. Formulation 1 showed a proinflammatory profile with potent capacity to increase IFNγ and TNFα, and potentiated the Spleen Index up to 2.05 in the GVDH model with p = 0.0002. Formulation 2 showed a suppressor/regulatory profile with potent capacity to increase IL-10 and TGFβ and suppress the production of TNFα. In the model used, this formulation suppressed the Spleen Index in a dose-dependent manner with high statistical significance. The known safety profile and absence of reactogenicity of both formulations was corroborated. Conclusions: Both formulations have potential application in the fields of GVHD therapy and other pathologies as well as in Vaccinology. The results obtained in the present work suggest the usefulness to continue with the pharmaceutical development and complete the preclinical studies of both formulations(AU)

Regulation of decellularized matrix mediated immune response.

The substantially growing gap between suitable donors and patients waiting for new organ transplantation has compelled tissue engineers to look for suitable patient-specific alternatives. Lately, a decellularized extracellular matrix (dECM), obtained primarily from either discarded human tissues/organs or other species, has shown great promise in the constrained availability of high-quality donor tissues. In this review, we have addressed critical gaps and often-ignored aspects of understanding the innate and adaptive immune response to the dECM. Firstly, although most of the studies claim preservation of the ECM ultrastructure, almost all methods employed for decellularization would inevitably cause a certain degree of disruption to the ECM ultrastructure and modulation in secondary conformations, which may elicit a distinct immunogenic response. Secondly, it is still a major challenge to find ways to conserve the native biochemical, structural and biomechanical cues by making a judicious decision regarding the choice of decellularization agents/techniques. We have critically analyzed various decellularization protocols and tried to find answers on various aspects such as whether the secondary structural conformation of dECM proteins would be preserved after decellularization. Thirdly, to keep the dECM ultrastructure as close to the native ECM we have raised the question "How good is good enough?" Even residual cellular antigens or nucleic acid fragments may elicit antigenicity leading to a low-grade immune response. A combinative knowledge of macrophage plasticity in the decellularized tissue and limits of decellularization will help achieve the native ultrastructure. Lastly, we have shifted our focus on the scientific basis of the presently accepted criteria for decellularization, and the effect on immune response concerning the interaction between the decellularized extracellular matrix and macrophages with the subsequent influence of T-cell activation. Amalgamating suitable decellularization approaches, sufficient knowledge of macrophage plasticity and elucidation of molecular pathways together will help fabricate functional immune informed decellularized tissues in vitro that will have substantial implications for efficient clinical translation and prediction for in vivo reprogramming and tissue regeneration.

Donor-Specific Human Leukocyte Antigen Antibody Formation After Distal Tibia Allograft and Subsequent Graft Resorption.

The association between donor-specific human leukocyte antigen (HLA) antibody formation and small bone allograft resorption has not been studied. We present the case of a patient treated for glenoid bone loss using a distal tibial allograft with Bankart repair who formed donor-specific HLA antibodies against the allograft and had subsequent graft resorption. X-ray and computed tomography (CT) scans were performed before and after surgery at standard checkpoints. Patient blood and serum samples were collected before and after surgery for HLA typing and HLA antibody testing. Human leukocyte antigen antibodies against the donor-specific HLA-A2 antigens were identified 6 weeks after surgery and were still detected at 5 months after surgery. At 6 months after surgery, a CT arthrogram revealed significant graft resorption. This case shows a temporal correlation between HLA antibody formation and clinical findings, potentially suggesting an association between HLA antibody formation and graft resorption. Further study is required to confirm this.

Obesity in the Liver Transplant Setting.

The obesity epidemic has resulted in an increased prevalence of obesity in liver transplant (LT) candidates and in non-alcoholic fatty liver disease (NAFLD) becoming the fastest growing indication for LT. LT teams will be dealing with obesity in the coming years, and it is necessary for them to recognize some key aspects surrounding the LT in obese patients. Obesity by itself should not be considered a contraindication for LT, but it should make LT teams pay special attention to cardiovascular risk assessment, in order to properly select candidates for LT. Obese patients may be at increased risk of perioperative respiratory and infectious complications, and it is necessary to establish preventive strategies. Data on patient and graft survival after LT are controversial and scarce, especially for long-term outcomes, but morbid obesity may adversely affect these outcomes, particularly in NAFLD. The backbone of obesity treatment should be diet and exercise, whilst being careful not to precipitate or worsen frailty and sarcopenia. Bariatric surgery is an alternative for treatment of obesity, and the ideal timing regarding LT is still unknown. Sleeve gastrectomy is probably the procedure that has the best evidence in LT because it offers a good balance between safety and efficacy.

Predicting kidney transplant outcomes with partial knowledge of HLA mismatch.

We consider prediction of graft survival when a kidney from a deceased donor is transplanted into a recipient, with a focus on the variation of survival with degree of human leukocyte antigen (HLA) mismatch. Previous studies have used data from the Scientific Registry of Transplant Recipients (SRTR) to predict survival conditional on partial characterization of HLA mismatch. Whereas earlier studies assumed proportional hazards models, we used nonparametric regression methods. These do not make the unrealistic assumption that relative risks are invariant as a function of time since transplant, and hence should be more accurate. To refine the predictions possible with partial knowledge of HLA mismatch, it has been suggested that HaploStats statistics on the frequencies of haplotypes within specified ethnic/national populations be used to impute complete HLA types. We counsel against this, showing that it cannot improve predictions on average and sometimes yields suboptimal transplant decisions. We show that the HaploStats frequency statistics are nevertheless useful when combined appropriately with the SRTR data. Analysis of the ecological inference problem shows that informative bounds on graft survival probabilities conditional on refined HLA typing are achievable by combining SRTR and HaploStats data with immunological knowledge of the relative effects of mismatch at different HLA loci.

IL17A and IL17F genes polymorphisms are associated with histopathological changes in transplanted kidney.

BACKGROUND: Interleukin 17 is a proinflammatory cytokine involved in immune response after allograft transplantation. IL-17 family of proinflammatory cytokines includes IL-17A and IL-17F. Previous studies have demonstrated that the rs2275913 IL17A and the rs11465553 IL17F gene polymorphism are associated with kidney allograft function. Because of the association between these polymorphisms and post-transplant immune response, we assume that these single nucleotide polymorphisms may affect morphological structure of transplanted kidney. The aim of this study was to examine the association of rs2275913 IL17A and rs2397084, rs11465553 and rs763780 IL17F gene polymorphisms with histopathological changes in transplanted kidney biopsies such as: glomerulitis, tubulitis, arteritis, cell infilitration and fibrosis. METHODS: The study enrolled 82 patients after renal graft transplantation in whom a kidney biopsy was performed because of impaired graft function. The rs2397084 T > C (Glu126Gly), rs11465553 G > A (Val155Ile) and rs763780 T > C (His167Arg) polymorphisms within the IL17F gene and the rs2275913 A > G (- 197 A > G) polymorphism within the IL17A gene promoter were genotyped using TaqMan genotyping assays on a 7500 FAST Real-Time PCR System (Applied Biosystems, USA). RESULTS: There was a significant association between the rs2275913 IL17A gene polymorphism and the grade of tubulitis, which was more severe among patients with the A allele, compared to recipients with the GG genotype (GG vs. AG + AA, P = 0.02), and with the grade of arteriolar hyaline thickening and mesangial matrix increase, which were more severe among patients with the G allele compared to recipients with the AA genotype (AA vs. AG + GG, P = 0.01 and P = 0.04, respectively). Tubular atrophy and interstitial fibrosis were more severe among individuals with the C allele at the rs763780 IL17F gene polymorphism (TT vs. TC, P = 0.09 and P = 0.017, respectively). However, it should be taken into account that the statistical significance was achieved without correction for multiple testing, and no significant association would remain significant after such correction. CONCLUSIONS: The results of this study may suggest a possible association between the rs2275913 IL17A and rs2275913 IL17A gene polymorphisms and some histopathological changes in transplanted kidney biopsies.

Allergy to Surgical Implants.

Surgical implants are essential elements of repair procedures to correct worn out joints, damaged spinal components, heart and vascular disease, and chronic pain. However, many of the materials that provide stability, flexibility, and durability to the implants are also immunogenic. Fortunately, allergic responses to surgical implants are infrequent. When they do occur, however, the associated pain, swelling, inflammation, and decreased range of motion can significantly impair the implant function. Given the high numbers of joint replacements performed in the developed world, allergic reactions to orthopedic implants form the largest category of allergic responses. The most important allergens in this category include nickel, cobalt, chromium, and bone cement. These allergens are also the most important in reactions to spinal surgeries. Multiple cardiac and neurostimulatory devices are constructed of metals and adhesives that can be sensitizing in some individuals. Implantable pulse generators, important in cardiac pacemakers, gastric stimulators, and neurostimulators, may include components made of stainless steel, titanium alloy, platinum and iridium, epoxy resins, poly methyl methacrylates, and isocyanates, all of which are immunogenic in some patients. Cardiac stents and patches are often made of Nitinol, a composite of nickel and titanium. More surgical procedures are closed using skin glues, which are also capable of triggering a blistering contact dermatitis. Patch testing is the gold standard to determine sensitization, and this review provides a list of standard allergens to test for different implants. The patients most appropriate for testing include (1) pre-operative joint replacement patients with a prior history of skin reactions to metal jewelry, jean snaps, watch bands, metal glass frames, artificial nails, or skin glue; (2) post-operative joint replacement failure patients needing revision without an obvious cause such as infection or mechanical incompatibility; and (3) post-operative cardiac or neurological patients with localized rash, pain, swelling, or inflammation near or over the implant.

Biocompatibility of polyamide 12 intramedullary rod after humeral consolidation in white Plymouth Rock birds / Biocompatibilidade de haste intramedular bloqueada de poliamida 12 após consolidação óssea umeral em aves Plymouth Rock branca

Technological and tissue engineering have enabled available, biologically inert, and low cost materials to be considered as viable alternatives in the surgical treatment of long bone fractures in birds. The aim of this study was to microscopically analyse osteotomized humerus of birds following the insertion of solid laser-sintered polyamide 12 rods in order to detect foreign body reaction and, thus, verify the bioinert property of the material in the bone fracture environment. Polyamide 12 intramedullary rods were inserted into the osteotomized humerus of 10 birds (white Plymouth Rock) and blocked using 2mm diameter cortical screws of varying lengths. The birds were operated at 60 days of age and monitored post-operatively for three months. Animals were euthanized at 150 days old and samples of the operated humerus collected for immunohistochemistry, light and scanning electron microscopy analysis. Results show bone consolidation without rejection of the implant and absence of inflammatory cells. Vascular Endothelial Growth Factor (VEGF) was expressed in the endothelial cells of the blood vessels at the site of the newly formed bone surrounding the implant, indicative of local angiogenesis. There was no bone growth on the surface of the rod; however, the implant did not interfere with the circumjacent bone repair. Thus, the findings of this study corroborate with the literature in characterizing polyamide as a bioinert material and, under the studied conditions, it can be concluded that polyamide 12 intramedullary rod is biocompatible and provides adequate bone consolidation in humeral fractures with no signs of rejection.(AU)

Com o desenvolvimento tecnológico e crescimento da engenharia de tecidos, o uso de materiais disponíveis, bioinertes e debaixo custo pode ser alternativa viável para o tratamento cirúrgico de fraturas em ossos longos nas aves. O objetivo do estudo foi realizar avaliação microscópica óssea após a implantação de haste maciça de poliamida, implantada em úmeros osteotomizados de galinhas para detectar reação do tipo corpo estranho, verificando a propriedade "bioinerte" do material no ambiente de fratura óssea. Foram utilizados 10 galos (Plymouth rock branca) e implantou-se a haste perfazendo o bloqueio das mesmas com parafusos corticais de 2 mm de diâmetro com comprimentos de acordo com a necessidade. As aves foram operadas aos 60 dias de vida e o acompanhamento pós-operatório ocorreu por três meses. Após a eutanásia, foram realizadas coletas do úmero operado (local de consolidação óssea) paraexame histopatológico, imuno-histoquímico e de microscopia eletrônica de varredura. Os resultados demonstraram consolidação óssea, sem presença de rejeição do material, com ausência de células inflamatórias. A neoformação óssea ao redor do implante expressou VEGF (fator de crescimento endotelial vascular) nas células endoteliais dos vasos sanguíneos caracterizando angiogênese no local. Na região de interface de tecido ósseo com a poliamida não foram observadas micro fraturas. Não houve crescimento ósseo na superfície da haste, porém a mesma não atrapalhou o reparo ósseo circunjacente. Assim, esse estudo corrobora com a literatura caracterizando a poliamida como um material bioinerte, e nas condições estudadas pode-se concluir que o uso da haste intramedular de poliamida 12 proporcionou consolidação óssea nesse modelo biológico nesse tipo de fratura, não havendo indícios de induzir rejeição.(AU)

Influenza vaccine strategies for solid organ transplant recipients.

PURPOSE OF REVIEW: The aim of this study was to highlight recent evidence on important aspects of influenza vaccination in solid organ transplant recipients. RECENT FINDINGS: Influenza vaccine is the most evaluated vaccine in transplant recipients. The immunogenicity of the vaccine is suboptimal after transplantation. Newer formulations such as inactivated unadjuvanted high-dose influenza vaccine and the administration of a booster dose within the same season have shown to increase response rates. Intradermal vaccination and adjuvanted vaccines did not show clear benefit over standard influenza vaccines. Recent studies in transplant recipients do not suggest a higher risk for allograft rejection, neither after vaccination with a standard influenza vaccine nor after the administration of nonstandard formulation (high-dose, adjuvanted vaccines), routes (intradermally) or a booster dose. Nevertheless, influenza vaccine coverage in transplant recipients is still unsatisfactory low, potentially due to misinterpretation of risks and benefits. SUMMARY: Annual influenza vaccination is well tolerated and is an important part of long-term care of solid organ transplant recipients.

Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras.

Allogeneic hematopoietic stem cell transplantation is an emerging treatment option for solid tumors because of its capacity to elicit immune graft-versus-tumor effects. However, these are often limited and associated with GvHD. Adoptive recipient leukocyte infusion (RLI) was shown to enhance anti-tumor responses of allogeneic bone marrow transplantation in murine neuroblastoma (Neuro2A)-bearing chimeras. In contrast to the clinically used donor leukocyte infusion, the RLI anti-tumor effect-elicited by host-versus-graft lymphohematopoietic reactivity-does not cause GvHD; however, the tumor growth-inhibitory effect is incomplete, because overall survival is not prolonged. Here, we studied the anti-solid tumor mechanisms of RLI with the objective to improve its efficacy. Host-versus-graft reactivity following RLI was associated with a systemic cytokine storm, lymph node DC activation, and systemic expansion of host-derived IFN-γ-expressing CD4+ T cells and IFN-γ-and granzyme B-expressing CD8+ T cells, which acquired killing activity against Neuro2A and third-party tumor cells. The tumor showed up-regulation of MHC class I and a transient accumulation of IFN-γ-and granzyme B-expressing CD8+ T cells: the intra-tumor decline in cytotoxic CD8+ T cells coincided with a systemic-and to a lesser extent intra-tumoral-expansion of MDSC. In vivo MDSC depletion with 5-FU significantly improved the local tumor growth-inhibitory effect of RLI as well as overall survival. In conclusion, the RLI-induced alloreactivity gives rise to a host-derived cytotoxic T-cell anti-neuroblastoma response, but also drives an expansion of host-type MDSC that counteracts the anti-tumor effect. This finding identifies MDSC as a novel target to increase the effectiveness of RLI, and possibly other cancer immunotherapies.

Establishment of calculated panel reactive antibody and its potential benefits in improving the kidney allocation strategy in Taiwan.

BACKGROUND/PURPOSE: Renal transplant candidates who are highly sensitized to human leukocyte antigens (HLAs) tend to wait longer to find a matched donor and have poor outcomes. Most organ-sharing programs prioritize highly sensitized patients in the allocation scoring system. The HLA sensitization status is traditionally evaluated by the panel-reactive antibody (PRA) assay. However, this assay is method dependent and does not consider the ethnic differences in HLA frequencies. A calculated PRA (cPRA), based on a population's HLA frequency and patients' unacceptable antigens (UAs), correctly estimates the percentage of donors suitable for candidates. The Taiwan Organ Registry and Sharing Center does not prioritize sensitized patients. We propose that the incorporation of the cPRA and UAs into the renal allocation program will improve the local kidney allocation policy. METHODS: We established a cPRA calculator using 6146 Taiwanese HLA-A, -B, -C, -DR, and -DQ phenotypes. We performed simulated allocation based on the concept of acceptable mismatch for 76 candidates with cPRA values exceeding 80%. RESULTS: We analyzed 138 waitlisted renal transplant candidates at our hospital, and we determined that the concordance rate of the cPRA and PRA for highly sensitized (%PRA > 80%) candidates was 92.5%, which decreased to 20% for those with %PRA < 80%. We matched 76 highly sensitized patients based on acceptable mismatch with the HLA phenotypes of 93 cadaver donors. Forty-six patients (61%) found at least one suitable donor. CONCLUSION: The application of the cPRA and acceptable mismatch can benefit highly sensitized patients and reduce positive lymphocyte cytotoxicity crossmatch.

Elderly living donor kidney transplantation allows worthwhile outcomes: The Japan Academic Consortium of Kidney Transplantation study.

OBJECTIVE: To compare transplant outcomes among elderly (aged ≥60 years) and non-elderly recipients, and to evaluate the acceptability of elderly living donor kidney transplantation in practice after consideration of living donor type. METHODS: We included 830 adult patients with living donor kidney transplantation between 2000 and 2011 in this retrospective cohort study. We compared death-censored graft survival, patient survival, biopsy-proven rejection, complications, and renal function in elderly (n = 119) and non-elderly recipients (n = 278). RESULTS: There was no significant difference in 10-year death-censored graft survival (P = 0.980). Corresponding patient survival rates in the elderly and non-elderly groups were 84.1% and 98.1%, respectively (hazard ratio 6.15, 95% confidence interval 2.12-17.82, P < 0.001). Elderly patients had more complications and chronic T-cell-mediated rejection. Factors associated with death in elderly recipients with functioning grafts were residual advanced recipient age (hazard ratio 1.39), decreased hemoglobin (hazard ratio 4.10), hepatitis B virus (hazard ratio 7.89), hepatitis C virus (hazard ratio 13.12) and elevated alanine aminotransferase (hazard ratio 1.13). CONCLUSIONS: Elderly living donor kidney transplantation seems to provide adequate acceptable outcomes. However, physicians should be cautious when evaluating elderly patients with hepatitis, and further studies are required to improve long-term outcomes.

Operational tolerance in kidney transplantation and associated biomarkers.

In the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients - i.e. patients who maintain allograft function in the absence of immunosuppression - are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, non-antigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective - identifying tolerant patients, enabling tolerance trials - as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.

Defining the immunogenicity and antigenicity of HLA epitopes is crucial for optimal epitope matching in clinical renal transplantation.

Transplantation of an human leukocyte antigen (HLA) mismatched graft can lead to the development of donor-specific antibodies (DSA), which can result in antibody mediated rejection and graft loss as well as complicate repeat transplantation. These DSA are induced by foreign epitopes present on the mismatched HLA antigens of the donor. However, not all epitopes appear to be equally effective in their ability to induce DSA. Understanding the characteristics of HLA epitopes is crucial for optimal epitope matching in clinical transplantation. In this review, the latest insights on HLA epitopes are described with a special focus on the definition of immunogenicity and antigenicity of HLA epitopes. Furthermore, the use of this knowledge to prevent HLA antibody formation and to select the optimal donor for sensitised transplant candidates will be discussed.