Plasma cell rich acute rejection: Risk factors, treatment and outcomes.

Plasma cell-rich rejection is a rare and poorly defined entity. Its treatment is not clearly defined and has universally poor prognosis. More data should be published from various transplant centers around the world to identify the treatment that has the best outcomes and to formulate treatment guidelines for these cases. It is a retrospective analysis of kidney biopsies form 2008 to 2018. Four hundred biopsied were screened and 55 were found to have features of rejection and among them, 13 had plasma cell-rich rejection. Data of treatment given and the graft survival outcomes in these cases were retrieved by medical records. One patient had complete recovery, three had graft loss and the remaining nine had permanent decline in glomerular filtration rate. Decrease in immunosuppression and presence of infection are risk factors for plasma cell-rich acute rejection (PCAR). It can be acute cell-mediated rejection (ACR)/antibody-mediated rejection (AMR)/ACR+AMR. Resistant rejection, ACR+AMR, C4d positivity, and severe interstitial inflammation are poor prognostic factors. Overzealous decrease in immunosuppression should not be done. Management of immunosuppression during infection is most critical for the development of PCAR. Bortezomib is emerging as a therapeutic modality for the treatment of PCAR.

Therapies for cardiac light chain amyloidosis: An update.

Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. This serious disorder is characterized by the presence of a clone of bone marrow plasma cells that produces monoclonal light chains (LCs) of the κ or predominantly λ type. These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that deposit within tissues. The lethal consequences of AL amyloidosis are due to the toxic products (the LCs) and not to the malignant behaviour of the plasma cell clone. Almost 80% of patients with AL amyloidosis have some degree of cardiac involvement, manifesting as heart failure (HF), and carrying a particularly poor prognosis. The past decade has seen major advances in the treatment of AL amyloidosis, and a rapidly fatal disease has become a treatable and possibly curable condition. The number of therapeutic options is rapidly expanding, offering hope to address currently unmet needs (most notably, the treatment of frail patients). The treatment of AL amyloidosis consists in a combination of agents targeting multiple steps of the amyloid cascade, associated with effective HF management, and there is ground for hope for dramatically improving the outcome in the near future. In the present review we will summarize our current knowledge on therapy for cardiac AL amyloidosis, targeting clinical cardiologists involved in the care of this serious disorder.

The use of animal models in multiple myeloma.

In myeloma, the understanding of the tissular, cellular and molecular mechanisms of the interactions between tumor plasma cells and bone cells have progressed from in vitro and in vivo studies. However none of the known animal models of myeloma reproduce exactly the human form of the disease. There are currently three types of animal models: (1) injection of pristane oil in BALB/c mice leads to intraperitoneal plasmacytomas but without bone marrow colonization and osteolysis; (2) injection of malignant plasma cell lines in immunodeficient mice SCID or NOD/SCID; the use of the SCID-hu or SCID-rab model allows the use of fresh plasma cells obtained from MM patients; (3) injection of allogeneic malignant plasma cells (5T2MM, 5T33) in the C57BL/KalwRij mouse induces bone marrow proliferation and osteolytic lesions. These cells did not grow in vitro and can be propagated by injection of plasma cells isolated from bone marrow of a mouse at end stage of the disease into young recipient mice. The 5TGM1 is a subclone of 5T33MM cells and can grow in vitro. Among the different models, the 5TMM models and SCID-hu/SCID-rab models were extensively used to test pathophysiological hypotheses and to assess anti-osteoclastic, anti-osteoblastic or anti-tumor therapies in myeloma. In the present review, we report the different types of animal models of MM and describe their interests and limitations.

Characterization of a novel mouse model of multiple myeloma and its use in preclinical therapeutic assessment.

To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCIDγc(null) mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment.

Plasmacytoid dendritic cells and immunotherapy in multiple sclerosis.

Plasmacytoid dendritic cells (pDCs) are specialized APCs implicated in the pathogenesis of many human diseases. Compared with other peripheral blood mononuclear cells, pDCs express a high level of TLR9, which recognizes viral DNA at the initial phase of viral infection. Upon stimulation, these cells produce large amounts of type I interferon and other proinflammatory cytokines and are able to prime T lymphocytes. Thus, pDCs regulate innate and adaptive immune responses. This article reviews select aspects of pDC biology relevant to the disease pathogenesis and immunotherapy in multiple sclerosis. Many unresolved questions remain in this area, promising important future discoveries in pDC research.

IRF-2 regulates B-cell proliferation and antibody production through distinct mechanisms.

Interferon regulatory factor (IRF)-2 is a transcription factor involved in type I (IFN- α/ß) signaling. It has been reported that IRF-2 deficiency results in various immune dysfunctions. However, the role of IRF-2 in B-cell functions needs to be elucidated. Unlike wild-type (WT) B cells, IRF-2(-/-) B2 cells were refractory to anti-IgM, but not LPS. Such a defect in proliferation was dependent on IFN- α/ß receptor (IFNAR). Marginal zone B cells increased in the proportion relative to B2 cells in IRF-2(-/-) mice produced IgM normally to LPS stimulation. However, IRF-2(-/-) B2 cells were defective in IgM production in an IFNAR-independent manner, although both B-cell subsets differentiated phenotypically to plasma cells at elevated efficiencies. Class switch recombination of IRF-2(-/-) B2 cells by LPS plus IL-4 was also impaired. Their reduced IgM production was conceivably due to an inefficient up-regulation of Blimp-1. Consistent with these in vitro observations, specific antibody production in vivo to a T-dependent antigen by B2 cells was severely impaired in IRF-2(-/- )mice. However, a low, but significant, level of IgG was detected at a late time point, and this IgG exhibited comparable binding affinity to that in WT mice. Follicular helper T-cell development and germinal center formation were normal. A similar tendency was observed when µ chain(-/-) mice were reconstituted with IRF-2(-/- )B cells. These results revealed a multi-faceted role of IRF-2 in the function of B cells, particularly B2 cells, through regulating proliferation in an IFNAR-dependent manner and antibody production via up-regulation of Blimp-1.

Autoreactive preplasma cells break tolerance in the absence of regulation by dendritic cells and macrophages.

The ability to induce Ab responses to pathogens while maintaining the quiescence of autoreactive cells is an important aspect of immune tolerance. During activation of TLR4, dendritic cells (DCs) and macrophages (MFs) repress autoantibody production through their secretion of IL-6 and soluble CD40L (sCD40L). These soluble mediators selectively repress B cells chronically exposed to Ag, but not naive cells, suggesting a means to maintain tolerance during TLR4 stimulation, yet allow immunity. In this study, we identify TNF-α as a third repressive factor, which together with IL-6 and CD40L account for nearly all the repression conferred by DCs and MFs. Similar to IL-6 and sCD40L, TNF-α did not alter B cell proliferation or survival. Instead, it reduced the number of Ab-secreting cells. To address whether the soluble mediators secreted by DCs and MFs functioned in vivo, we generated mice lacking IL-6, CD40L, and TNF-α. Compared to wild-type mice, these mice showed prolonged anti-nuclear Ab responses following TLR4 stimulation. Furthermore, adoptive transfer of autoreactive B cells into chimeric IL-6(-/-) × CD40L(-/-) × TNF-α(-/-) mice showed that preplasma cells secreted autoantibodies independent of germinal center formation or extrafollicular foci. These data indicate that in the absence of genetic predisposition to autoimmunity, loss of endogenous IL-6, CD40L, and TNF-α promotes autoantibody secretion during TLR4 stimulation.

Homing and adhesion patterns determine the cellular composition of the bone marrow plasma cell niche.

According to commonly held concepts, plasma cell (PC) longevity in bone marrow (BM) depends upon their access to survival niches. These are thought to exist in nursery cell types, which support PCs by secreting PC survival factors. To better define PC survival niches and their functioning, we adoptively transferred traceable Blimp-1-(GFP) PCs into recipient mice lacking a proliferation-inducing ligand (APRIL), IL-6, or macrophage migration inhibitory factor. Transferred BMPCs were preferentially associated with Ly-6C(high) monocytes (normalized colocalization index: 9.84), eosinophils (4.29), and megakaryocytes (2.12). Although APRIL was essential for BMPC survival, PC recruitment into the proximity of nursery cells was unimpaired in APRIL-deficient mice, questioning the concept that the same factors account for attraction/retention of PCs as for their local survival. Rather, the order of colocalization with BMPCs (monocytes > eosinophils > megakaryocytes) reflected these cells' relative expression of CXCR4, VLA-4, and LFA-1, the homing and adhesion molecules that direct/retain PCs in the BM. This suggests a scenario wherein the cellular composition of the BMPC niche is defined by a common pattern of attraction/retention on CXCL12-abundant reticular docking cells. Thereby, PCs are directed to associate in a functional BM niche with hematopoietic CXCR4(+)VLA-4(+)LFA-1(+) nursery cells, which provide PC survival factors.

Liver transplant quality and safety plan in anesthesia and intensive care medicine.

Patients scheduled for orthotopic liver transplantation (OLT) may have coexisting diseases and more likely receive grafts of poorer quality than in the past. Perioperative mortality and morbidity are usually due to a combination of factors related to the patient, graft, surgery, anesthesia, and intensive care management. Anesthesia and intensive care are the areas with the highest frequency and severity of errors. Error and accident risks are always present in this context where a human component is unavoidable. The matter of medical errors is becoming noteworthy worldwide. Nevertheless, data concerning medical errors during OLT are not available in Italy. There are only hypothetical evaluations. The number of adverse events may be high, but so far no specific programs have been developed to increase patient safety. To improve patient safety, anesthesia and intensive care units must use a proactive approach dedicated to an OLT program. We have presented herein a prevention policy to detect errors before they happen through incident reporting, anonymous and voluntary reports of adverse events or near misses, operating room checklists (patient, drugs, devices, equipment), improved training, safer facilities, equipment function, and adequate drug supplies for an OLT program.

Analysis of survival after primary liver transplantation: multivariate analysis of 155 cases in a single center.

Liver transplantation is known as a highly complex procedure. Several variables can affect the outcome. The present study is a retrospective multivariate analysis of the outcomes of primary liver transplant recipients from deceased donors. From November 2006 through January 2009, 155 patients received first liver transplants from deceased donors. The data included the following: age of the recipient, gender of the recipient, ABO type, indication for the transplantation, model for end-stage liver disease (MELD) score, operative time, donor age, gender of the donor, cold ischemia time, and quantity of transfused blood products-red blood cells (PRBC), red blood cells recovered during the operation (cell saver), platelets, and fresh frozen plasma. Statistical analysis was done using SPSS 17 software. Cox regression analysis was performed to identify significant variables. ROC (receiver operating characteristic) curve was applied for those significant factors. Among all variables, only PRBC transfusion and MELD score showed statistical significance. For PRBC the increment of death risk was 17.08%, and for MELD score it was 3.83%. Patients that had to use PRBC and higher MELD scores had worse survivals. We concluded that the requirement for red blood cell transfusions and MELD showed the most significant influences on the outcomes of adult liver transplantations from deceased donors.

Delayed and deficient establishment of the long-term bone marrow plasma cell pool during early life.

Early life antibody responses are characterized by a rapid decline, such that antigen-specific IgG antibodies decline to baseline levels within months following infant immunization. This generic observation remains unexplained. Here, we have analyzed the induction and organ-localization of antigen-specific IgG antibody-secreting cells (ASC) following immunization of 1-week-old or adult BALB/c mice with tetanus toxoid (TT), a T-dependent antigen. Early life priming induced only slightly lower numbers of TT-specific IgG ASC in the spleen, and these reached adult levels following repeat immunization. In contrast, early life immunization generated much fewer bone marrow plasma cells than in adults, even after boosting. A similar limitation of the natural development of the bone marrow pool of ASC was observed. Transfer experiments with adult or early life spleen ASC indicated limited homing of TT-specific adult ASC to the bone marrow of 4-week-old mice as compared to adult recipients, whereas homing patterns were similar when early life or adult ASC were transferred into adult recipients. These observations suggest that a limited bone marrow B cell homing capacity and, as a result, relatively deficient bone marrow ASC responses, are critical factors which may explain the limited persistence of IgG antibodies to T-dependent antigens in early life.

Murine plasmacytomas, carrier of the t(12;15) chromosomal translocation, develop from immature/mature B cells not from differentiated plasma cells.

Dysregulation of the c-myc gene by chromosomal translocation in >95% of murine plasmacytomas (MPCs) is an obligatory requirement for the transformation of B lymphocytes into MPCs. However, it is still unknown whether sIg+ B cells or differentiated plasma cells are the legitimate precursor cells from which MPCs develop. To address this question, C.B-17 scid/scid (SCID) mice were reconstituted with splenic surface Ig-positive (sIg+) B lineage cells originating from BALB/cRb6.15 (B/cRb6.15) or human IL-6 transgene-congenic BALB/cRb8.12 mice (B/cRb8.12 IL-6-Tg). Six of 80 SCID mice reconstituted with B/cRb6.15 sIg+ B cells developed MPCs after pristane (2,6,10,14-tetramethylpentadecane) treatment followed by Abelson murine leukemia virus (A-MuLV) infection (incidence 7.5%) and four of 40 after pristane treatment alone (incidence 10%). Similarly, in 20 SCID mice reconstituted with B/cRb8.12 IL-6-Tg splenic sIg+ B cells the MPC incidence was 10%. Karyotype analysis revealed that all the translocations were of typical t(12;15) type and all tumors carried the Rb6.15 or Rb8.12 marker chromosome, indicating their donor cell origin. In contrast, none of the 48 SCID mice reconstituted with plasma cells obtained from the lymph nodes of B/cRb8.12 IL-6-Tg mice developed MPCs when treated either with pristane plus A-MuLV (20 mice) or with pristane alone (28 mice), although the transferred plasma cells were still functional in the recipient SCID mice 6 months after transfer. The findings indicate that the malignant transformation triggered by Ig/myc juxtaposition occurs more in immature (sIgM+) and/or mature (sIgM+/sIgD+, sIgG+ and sIgA+) B cells than in differentiated G0 or cycling plasma cells. We inferred that immature and/or mature B cells and not differentiated plasma cells are most likely the principal source of precursor cells from which the typical t(12;15) MPCs develop.

Salivary immunoglobulins in recipients of bone marrow grafts. III. A longitudinal follow-up of CMV specific antibodies.

Cytomegalovirus (CMV) infection is a major complication of BMT. The oral cavity is a common route for CMV infection, whose protection is provided by salivary anti-CMV antibodies. We developed an ELISA assay for the detection of CMV-specific antibodies in parotid saliva. Saliva of patients receiving BMT from CMV-positive donors was transiently reconstituted with IgG and IgA anti-CMV antibodies shortly after transplantation. The concentration of these antibodies gradually decreased during the 2 months after transplantation and increased again around day 80. A remarkable rise in the salivary concentrations of IgG and IgM anti-CMV was observed shortly after i.v. administration of Sandoglobulin. These results demonstrate, for the first time accurate monitoring of CMV-specific antibodies in saliva using a quantitative ELISA assay. The study suggests that secretion of CMV-specific antibodies in saliva of immunocompromised patients can be reconstituted by donor-derived B and plasma cells transferred with the BM or by i.v. administration of pooled Ig.

The secretory IgA system of the gut.

Most commonly, humoral immunity manifested in the gastrointestinal tract of mammals is due to the presence of secretory IgA antibodies. Antibody specificities have been detected in the secretory IgA of gut secretions to a wide range of naturally occurring viral and bacterial components and to test antigens such as chemically modified proteins. Much of the IgA found in gut secretions is synthesized and secreted locally by the abundant plasma cells of the lamina propria. Development of methods for establishing local protective immunity in the gut requires knowledge of the origins of these plasma cells and of the whereabouts of their precursors when they are susceptible to antigen-driven proliferation and/or maturation. The Peyer's patches have been shown to contain a population of B lymphocytes especially rich in precursors for IgA plasma cells and in cells which can repopulate gut lamina propria with such IgA plasma cells. The Peyer's patches also appear to 'sample' gut antigens, in that small amounts of antigens are passed intact through their dome epithelial cells. Recent experiments bearing on the origins, differentiation and maturation, antigen sensitivity, migration and lodging of precursors for gut IgA plasma cells are discussed. We use the following three systems: (1) congenic transfer of cells from different murine lymphoid cell sources or mixtures of these (CB20 leads to BALB/c or BALB/c leads to CB20) and the use of allo-antisera to IgA allotypic determinants to assess their potential to impart an adoptive IgA antibody response to the recipient and to repopulate its histocompatible lamina propria with IgA plasma cells; (2) clonal precursor analysis (the method of Klinman) both to enumerate antigen-sensitive cells in different tissues of mice and to evaluate their potential to generate plasma cells making particular isotypes and idiotypes of antibodies; (3) use of pairs of Thiry-Vella loops in rabbits, each member either bearing or lacking a Peyer's patch, and quantitation of antibodies of each isotype and of total secretory IgA to assess the response of each loop with the time after local immunization. The results from all three systems provide strong evidence for the importance of Peyer's patches in supplying cells responsible for local humoral immunity and suggest both a differentiative pathway for IgA precursors and their whereabouts when antigen may cause the expansion of a population of specific cells.