Revisiting the liver’s role in transplant alloimmunity

The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation.This phenomenon was observed nearly five decades ago.Subsequently,the liver’s role in multivisceral transplantation was recognized,as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart.The liver has a unique architecture and is home to many cells involved in immunity and inflammation.After transplantation,these cells migrate from the liver into the recipient.Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system.Recent studies on human T-cell subtypes,cytokine expression,and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation.In this article,we discuss the privileged state of liver transplantation compared to other solid organ transplantation,the liver allograft’s role in multivisceral transplantation,various cells in the liver involved in immune responses,and the potential mechanisms underlying immunomodulation of host alloresponses.

Extracellular vesicles as mediators of alloimmunity and their therapeutic potential in liver transplantation

Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell types.They are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins,lipids,and nucleic acids.In the last two decades,wide-ranging evidence has established the involvement of EVs in the regulation of immunity,with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory,autoimmune,and infectious disease pathology.More recently,studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation,with EVs shown to be capable of eliciting allograft rejection as well as promoting tolerance.These insights are necessitating the reassessment of standard paradigms of T cell alloimmunity.In this article,we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical transplantation.Furthermore,we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.

Is de novo membranous nephropathy suggestive of alloimmunity in renal transplantation?A case report

BACKGROUND Post-transplant nephrotic syndrome(PTNS)in a renal allograft carries a 48%to 77%risk of graft failure at 5 years if proteinuria persists.PTNS can be due to either recurrence of native renal disease or de novo glomerular disease.Its prognosis depends upon the underlying pathophysiology.We describe a case of post-transplant membranous nephropathy(MN)that developed 3 mo after kidney transplant.The patient was properly evaluated for pathophysiology,which helped in the management of the case.CASE SUMMARY This 22-year-old patient had chronic pyelonephritis.He received a living donor kidney,and human leukocyte antigen-DR(HLA-DR)mismatching was zero.PTNS was discovered at the follow-up visit 3 mo after the transplant.Graft histopathology was suggestive of MN.In the past antibody-mediated rejection(ABMR)might have been misinterpreted as de novo MN due to the lack of technologies available to make an accurate diagnosis.Some researchers have observed that HLA-DR is present on podocytes causing an anti-DR antibody deposition and development of de novo MN.They also reported poor prognosis in their series.Here,we excluded the secondary causes of MN.Immunohistochemistry was suggestive of IgG1 deposits that favoured the diagnosis of de novo MN.The patient responded well to an increase in the dose of tacrolimus and angiotensin converting enzyme inhibitor.CONCLUSION Exposure of hidden antigens on the podocytes in allografts may have led to subepithelial antibody deposition causing de novo MN.

Management of the Prevention of the Rhesus Alloimmunization: Case of the Mother-Child Hospital Dominique Ouattara of Bingerville/Ivory Coast/West Africa

Introduction: Perinatal mortality linked to fetal anemia of red cell alloimmunization in Côte d’Ivoire as in many developing countries can be explained by a lack of knowledge of Rhesus D feto-maternal alloimmunization, hence the obvious importance of carrying out a study on the problem of prevention of alloimmunization in rhesus negative births. This study takes stock of the management of this pathology in a reference hospital. Results and Discussion: Rh-negative mothers account for 6% of births, 42.7% (70/164) of women had a history of risk, about 61% of women had not had proper prophylaxis during previous pregnancies;and as many had not had follow-up of the coombs test during the current pregnancy;only 4.9% of patients had systematic prophylaxis with anti D serum at 28 weeks of pregnancy. This low rate of prevention is related to the financial difficulties of the patients, but also to a lack of knowledge of the pathology by the nursing staff. Conclusion: Good management of rhesus negative women during their pregnancy allows their incompatible child to benefit from all current treatments ensuring a healthy birth. It is therefore important for medical personnel to know how to deal with this rare disease in a small proportion of pregnant women.

Chimeric Antigen Receptors and Regulatory T Cells:The Potential for HLA-Specific Immunosuppression in Transplantation

Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by the inclusion of an antigen-specific binding region within the synthetic CAR construct.The advantage of cells with programmed specificity has been demonstrated clinically in the field of oncology,and it is clear that such cells have greater accuracy,potency,and reduced off-target therapeutic effects compared with their unmodified counterparts.In contrast to conventional T cells(Tconvs),regulatory T cells(Tregs)play a major role in suppressing immune activation and regulating the host immune response.CAR expression within Tregs has been proposed as a therapy for autoimmune and inflammatory diseases,graft-versus-host disease(GVHD),and organ transplant rejectio n.In the latter,they hold immense potential as mediators of immune tolerance for recipients of allotransplants.However,current research into CAR-Treg engineering is extremely limited,and there is uncertainty regarding optimal design for therapeutic use.This review examines the rationale behind the development of CAR-Tregs,their significance for human transplantation,potential designs,safety considerations,and comparisons of CAR-Tregs in transplantation models to date.

Essential concept of transplant immunology for clinical practice

Our understanding of transplant immunology has advanced from gross allograft rejection to cellular response and to current molecular level. More sensitive assays have been developed to characterize patient sensitization and to detect pre-existing donor-specific antibodies(DSA) in pre-transplant crossmatch. After a transplant, pre-existing or de novo DSA are increasingly monitored to guide clinical management. Therefore, it is important for clinicians to understand the basic concepts and key components of transplant immunology as well as be familiarized with the modern immunological techniques used in kidney transplantation.

Expression of AIF-1 and RANTES in Unexplained Spontaneous Abortion and Possible Association with Alloimmune Abortion

Objective To investigate the effects of allograft inflammatory factor-1 （AIF-1） and （RANTES） in sera and deciduas on unexplained early spontaneous abortion. Methods AIF-1 and RANTES were examined in sera and deciduas/endometria of 43 unexplained early spontaneous abortion women （group A）, 40 healthy women with early pregnancy（group B） and 20 healthy women with no pregnancy （group C）. Immunohistochemistry and enzyme linked immunosorbent assay （ELISA） were used in this study. Results AIF-1 protein was expressed both in deciduas of group A and in endometria of group C. In group A, H scores in the recurrent abortion deciduas specimens were significantly greater than those in the first abortion;in endometrium, expression of AIF-1 was greater in the secretory than in proliferative phase of group C. In group B, concentrations of RANTES in sera were higher in 7th-8th week of pregnancy than in 6th-7th and 〉8th week of pregnancy; expression of AIF-1 protein showed a negative correlation with RASNTES concentration; a significant increase of the RANTES levels in sera and tissue was observed in group B. Conclusion These results demonstrate, for the first time, that AIF-1 are expressed in deciduas of unexplained spontaneous abortion suggesting that AIF-1 involve in alloimmune abortion; RANTES might act as a novel blocking antibody;AIF-1 and RANTES might act as reliable markers for diagnosis of early alloimmune abortion.

THE EFFECT OF THE TRANSFER OF LAK CELLS, COMBINED WITH ALLOIMMUNIZATION, ON THE PULMONARY METASTASES OF RAT MAMMARY CARCINOMA

Alloimmunization was combined with lympho-kine activated killer (LAK) cells to assess its effect on mammary carcinoma in rats. The animals were injected with both irradiated allosplenocytes and syngeneic LAK cells. Metastatic lung nodules were markedly reduced using combined therapy when compared with the transfer of LAK cells or alloimmuni-zation alone. IL-2 activity in the serum of alloim-munized rats could be detected. This activity, maintained in vivo for one week, may be responsible for enhancing the antitumor effect of transferred LAK cells.

CD98 modulates alloimmune responses:evidence from the CD98-deficient mouse

CD98 heavy chain（CD98hc）,encoded by Slc3a2,is a widely expressed vertebrate membrane protein whose functions are known as facilitating amino acid transporter and mediating integrin signaling.Little is known about its function on T lymphocyte mediated immune response to alloantigen. Here we report that we successfully deleted CD98hc in T cells by crossing mice bearing a loxP-flanked Slc3a2 allele with those expressing Cre re-combinase in T cells（CD4-Cre+）.T cell-specific deficient of CD98hc resulted in lower responses to alloantigen stimulation in mixed lymphocyte reaction assay.Heterotopic cardiac grafting was then performed from BALB/c（H-2Kd） to CD98hclox/-CD4-Cre+ /C57BL/6（H-2Kb） or control littermate C57BL/6 （B6） mice.We found that all CD98hclox/-CD4-Cre+ recipients had indefinite survival（MST:】100days, n=8）.In contrast,all littermate B6 recipients suffered acute rejection[MST:（7.4±0.5）d,n=12].In addition,the survival of the skin grafts from donor BALB/c mice to more than postoperative day （POD） 100 heart-bearing tolerant CD98hclox/-CD4- Cre+ recipients was significantly prolonged[MST: （15.2±2.2）d,n =5]compared that of the B6 mice [MST:（8.2±1.3）d,n=9].In consistent with graft survival, we found that the graft infiltration cells on POD7 were fewer than that of the B6 mice by FACS and immune-staining analysis.Also chemotaxis assay data revealed that the migrated CD98hclox/-CD4-Cre+ lymphocyte were less than that of B6 in the presence of different concentration of chemokines CCL2, CCL5,and CCL2 plus CCL5.In addition,a neutralizing antibody（clone 26-24）specific against CD98hc prolonged the graft survival[MST:（13.4±2.7）d,n=8; P=0.001]in the B6 recipients after they received the BALB/c mice heart.Hence our data indicated that T cell-specific deficient of CD98hc impaired proliferate in response to alloantigens and decreased migration ability result in inducing immune tolerance after cardiac transplantation.Moreover,the application of the blocked of CD98hc by monoclonal antibody is effective in the treatment of acute cardiac allograft rejection, which may be useful clinically in the future.

Neonatal Alloimmune Thrombocytopenia Due to Maternal Anti HPA1a Antibodies: Case Report and Management of Subsequent Pregnancy

Fetoneonatal alloimmune thrombocytopenia is an infrequent and severe disease that is unexpectedly found after an uncomplicated first pregnancy. Affected infants might show unexplained purpura, intracranial hemorrhage, and/or gastrointestinal or genitourinary hemorrhage. Nevertheless, in asymptomatic newborns the thrombocytopenia may be discovered incidentally. We describe a case report that highlights that the incidental diagnosis of FNAIT allows both properly managing the newborn, and detecting maternal anti-HPA1a antibodies in order to prevent the disease in subsequent pregnancies. A non-invasive treatment based on IVIgG allowed to this patient to prevent FNAIT in her second pregnancy.

Immune-related late-onset hemorrhagic cystitis post allogeneic hematopoietic stem cell transplantation

Background The pathophysiology of late-onset hemorrhagic cystitis （LOHC） is currently not well understood. The aim of this study was to analyze the alloimmune aetiology in the pathogenesis of LOHC post allogeneic hematopoietic stem cell transplantation （HSCT）. Methods A retrospective study was performed on the medical records of 11 patients with immune-related LOHC post allogeneic HSCT. The clinical characteristics, therapy, and outcomes of these patients were analyzed. Results The median time of onset was 42 days after HSCT （range 16-150 days） and the median duration of HC was 43 days （range 29-47 days）. All patients presented with prolonged HC for more than 35 days. Nine patients with evidence of cytomegalovirus （CMV） reactivation did not respond to anti-viral therapy even with CMV clearance in the urine post-therapy. Eleven patients with refractory HC received a low dose of corticosteroids and all patients went into complete remission. Conclusion Our data suggest that alloimmune injury is involved in the pathogenesis of HC in at least some patients and that specific therapy might improve the clinical outcome of hemorrhagic cystitis.

Recent advances in myeloid-derived suppressor cell biology

In recent years,studying the role of myeloid-derived suppressor cells(MDSCs)in many pathological inflammatory conditions has become a very active research area.Although the role of MDSCs in cancer is relatively well established,their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion.Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases.The following topics will be specifically focused upon:(1)definition and characterization of MDSCs;(2)whether all MDSC populations consist of immature cells;(3)technical issues in MDSC isolation,estimation and characterization;(4)the origin of MDSCs and their anatomical distribution in health and disease;(5)mediators of MDSC expansion and accumulation;(6)factors that determine the expansion of one MDSC population over the other;(7)the Yin and Yang roles of MDSCs.Moreover,the functions of MDSCs will be addressed throughout the text.

Pathogenesis,diagnosis,and treatment of recurrent spontaneous abortion with immune type

Recurrent spontaneous abortion(RSA),defined as three or more consecutive pregnancy losses before 20 weeks of gestation,is difficult to treat in the clinical setting.It affects 1%–5%of women of reproductive age.In the investigations of immunopathogenesis,diagnosis,and treatment of RSA since the late 1980s,it was found that RSA was associated with abnormal maternal local or systemic immune response.The pathogenesis of autoimmune RSA was mainly associated with antiphospholipid antibody(APA),while that of alloimmune RSA was due to the disturbance of maternofetal immunological tolerance.Systemic etiological screening process and diagnosis systems of RSA with immune type were developed,and anticardiolipin(ACL or ACA)+anti-β2-GP1 antibody combining multiple assays for effective diagnosis of RSA with autoimmune type was first established.According to the dynamic monitoring of clinical parameters before and during gestation,low-dose,short-course,and individual immunosuppressive therapy and lymphocyte immunotherapy for RSA with immune type were carried out.The outcomes of the offsprings of patients with RSA were followed up,and the safety and validity of the therapies were confirmed.The research achievement leads to great progress in the diagnosis and treatment of RSA in China.

Polymer-mediated immunocamouflage of red blood cells: Effects of polymer size on antigenic and immunogenic recognition of allogeneic donor blood cells

Developing a practical means of reducing alloimmunization in chronically transfused patients would be of significant clinical benefit. Immunocamouflaging red blood ceils （RBCs） by membrane grafting of methoxypoly（ethylene glycol） （mPEG） may reduce the risk of allo-immunization. The results of this study showed that antibody recognition of non-ABO antigens was sig- nificantly reduced in an mPEG-dose- and polymer size-dependent manner, with higher molecular weight mPEGs providing better immunoprotection. Furthermore, in vivo immunogenicity was significantly reduced in mice serially transfused with mPEG-modified xenogeneic （sheep; sRBCs）, allogeneic （C57B1/6）, or syngeneic （Balb/c） RBCs. Following a primary transfu- sion of sRBCs, mice receiving mPEG-sRBCs showed a 〉90% reduction in anti-sRBC IgG antibody levels. After two transfusions, mice receiving mPEG-sRBCs showed reductions of 〉80% in anti-sRBC IgG levels. Importantly, mPEG-modified autologous cells did not induce neoantigens or an immune （IgG or IgM） response. These data suggest that the global immuno- camouflage of RBCs by polymer grafting may provide a safe and cost-effective means of reducing therisk of alloimmunization.

Platelets and platelet alloantigens:Lessons from human patients and animal models of fetal and neonatal alloimmune thrombocytopenia

Platelets play critical roles in hemostasis and thrombosis.Emerging evidence indicates that they are versatile cells and also involved in many other physiological processes and disease states.Fetal and neonatal alloimmune thrombocytopenia(FNAIT)is a life threatening bleeding disorder caused by fetal platelet destruction by maternal alloantibodies developed during pregnancy.Gene polymorphisms cause platelet surface protein incompatibilities between mother and fetus,and ultimately lead to maternal alloimmunization.FNAIT is the most common cause of intracranial hemorrhage in full-term infants and can also lead to intrauterine growth retardation and miscarriage.Proper diagnosis,prevention and treatment of FNAIT is challenging due to insufficient knowledge of the disease and a lack of routine screening as well as its frequent occurrence in first pregnancies.Given the ethical difficulties in performing basic research on human fetuses and neonates,animal models are essential to improve our understanding of the pathogenesis and treatment of FNAIT.The aim of this review is to provide an overview on platelets,hemostasis and thrombocytopenia with a focus on the advancements made in FNAIT by utilizing animal models.