Proposal for the American Journal of Transplantation policy for review of ethical standards of clinical research involving live human subjects.
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Ethics, Research↗
Biomedical subjects
Jonathan S Bromberg
Publications and source records attributed to Jonathan S Bromberg.
Pre-donation assessment of kidneys by magnetic resonance angiography and venography: accuracy and impact on outcomes.
Reports on the accuracy of magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) in evaluating living donor renovasculature employ few patients or omit the consequences of inaccurate scans. We retrospectively compared intraoperative findings to MRA/MRV scans in 146 donor-recipient pairs. For detecting accessory arteries and early branching, MRA sensitivity was 57.6%, specificity 96.5%, false positive rate 3.5%, false negative rate 42.4%, positive predictive value 82.6%, negative predictive value 88.6% and overall accuracy 87.7%. By excluding clinically inconsequential accessory arteries, MRA sensitivity rose to 73.1%, specificity to 96.7% and overall accuracy to 92.5%. For MRVs, sensitivity was 56.2%, specificity 99%, false positive rate 1%, false negative rate 43.8%, positive predictive value 90%, negative predictive value 94.8% and accuracy 94.5%. Inaccurate scans were associated with prolonged donor and recipient operations and more frequently reconstructed arteries, but did not affect clinical outcomes. Because most missed accessory arteries are inconsequential, MRA is a useful, less invasive method for defining donor renovascular anatomy.
Adult↗
Reepithelialization of orthotopic tracheal allografts prevents rejection after withdrawal of immunosuppression.
Prior work has demonstrated that immunosuppressed orthotopic tracheal allografts undergo progressive reepithelialization over a 48-day period with recipient-derived tracheal epithelium. We hypothesized that reepithelialization of tracheal allografts would prevent rejection after withdrawal of immunosuppression. BALB/c murine tracheal grafts were transplanted orthotopically into either syngeneic or allogeneic C57/BL6 recipients. The recipients were either not immunosuppressed, immunosuppressed with cyclosporine A (10 mg/kg per day) continuously, or immunosuppressed for 48 days and then withdrawn from immunosuppression. The grafts were assessed for acute and chronic rejection 10 days and 50 days after immunosuppression withdrawal. The immunosuppressed allograft recipients maintained a ciliated epithelium acutely and chronically after immunosuppression withdrawal. Ten days after immunosuppression withdrawal, there was a mild cellular infiltrate, which resolved 50 days after withdrawal. Electron microscopy, lymphocyte subpopulation assays, and lamina propria analysis demonstrated that immunosuppression withdrawal did not result in tracheal allograft rejection. In vitro and in vivo assessments did not demonstrate evidence of systemic or local immune tolerance. We conclude that reepithelialization of orthotopic tracheal allografts with recipient-derived mucosa prevents rejection of allograft segments. Tracheal transplantation may require only transient immunosuppression, which can be withdrawn after tracheal reepithelialization.
Animals↗
Role of donor-derived monocyte chemoattractant protein-1 in murine islet transplantation.
Monocyte chemoattractant protein-1 (CCL2/MCP-1) is a proinflammatory chemokine produced by several cell types, including pancreatic islets. High levels of donor-derived CCL2 have been associated with poor islet allograft outcome in patients with type 1 diabetes; however, the causal relationship is unknown. The constitutive and inducible expression of chemokines and their receptors by pancreatic islets in vitro were investigated, specifically the role of donor-derived CCL2 in marginal mass murine islet transplantation. The results showed that inflammatory cytokine stimulation of islets induced de novo expression of CCL2, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP-10 and increased expression of CXCL2/macrophage-inflammatory protein-2. CCL2 mRNA and protein were highly expressed within 2 d in cultures. Transplantation of islets with high levels of CCL2 into syngeneic recipients led to a significantly greater influx of CCR2(+) cells and higher expression of monocyte/macrophage-associated inflammatory cytokines compared with low CCL2-donor islets. The level of pretransplantation CCL2 inversely correlated (P < 0.0001) with isograft function. In contrast, in CCR2-/- recipients, this correlation was not present. A direct toxic effect of CCL2 on islets was excluded by assessing cell viability and insulin release in vitro. In conclusion, CCL2 secreted by islets plays an important role in the immediate islet graft function. Strategies to decrease islet-derived CCL2 release may increase the success of islet transplantation.
Animals↗
FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments.
FTY720 stimulates CCR7-driven T cell homing to peripheral lymph nodes (LN) by direct activation of sphingosine 1-phosphate receptors, along with the participation of multidrug transporters, 5-lipoxygenase, and G protein-coupled receptors for chemokines. In this study, we demonstrate that FTY720 also directly stimulates in vitro T cell chemotaxis to CCR2-CCL2, but not to a variety of other chemokines, including CCR5-CCL3/4/5 and CXCR4-CXCL12. FTY720 influences CCR2-CCL2-driven migration through activation of the multidrug transporters, Abcb1 and Abcc1, and through 5-lipoxygenase activity. In vivo administration of FTY720 induces chemokine-dependent migration of T cells in the thymus, peripheral blood, LN, and spleen. The CCR7 and CCR2 chemokine ligands are required for both T cell sequestration in LN and thymic T cell egress following FTY720 administration. Furthermore, FTY720 administration uncovers a requirement for CXCR4 ligands for LN homing, but not for thymic egress, and CCR5 for thymic egress, but not LN homing. FTY720-driven splenic and peripheral blood T cell egress are both independent of CCR2, CCR5, CCR7, or CXCR4. These results indicate that FTY720- and sphingosine 1-phosphate receptor-stimulated T cell migration are dependent on the restricted usage of chemokine receptor-ligand pairs within discrete anatomic compartments.
Animals↗
The beginnings of T-B collaboration.
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Animals↗
Therapeutic manipulation of T cell chemotaxis in transplantation.
T cell migration and trafficking are regulated by the well defined cellular processes of rolling, activation, tight adhesion, arrest and diapedesis. These processes are, in turn, controlled by molecular events involving integrins, selectins, chemokines and chemokine receptors. Recent studies have shown that sphingosine 1-phosphate receptors and their ligands are also important molecular modulators of migration and trafficking. Many of these molecules are appropriate targets for preventing allograft rejection or for achieving tolerance. Studies of migration and trafficking have also shown that the anatomic choreography of alloantigen presentation and T cell encounter with alloantigen and immunosuppression, are over-riding determinants of T cell priming versus tolerization.
Animals↗
Post-liver transplant acute renal failure: factors predicting development of end-stage renal disease.
BACKGROUND: Acute renal failure (ARF) occurs in 5-50% of patients undergoing orthotopic liver transplantation (OLT). The aim of this study was to determine factors that might predict the development of end stage renal disease (ESRD) in patients who had ARF after OLT. METHODS: We studied all OLT recipients between 9/1/1988 through 12/31/2000. RESULTS: A total of 1602 patients underwent OLT during the study period. About 350 patients (22%) developed ARF requiring dialysis post-operatively. One hundred and twenty-three (39.8%) died within a year after OLT. Median follow up was 5.8 yr (range 1-12 yr). Forty-three patients (23%) developed ESRD over median of 3.79 yr (range 1-8 yr). Multivariate logistic regression analysis revealed creatinine levels > 1.7 mg/dL at 1 yr (p < 0.001), cyclosporine as immunosuppression (p = 0.026), and the presence of diabetes pre-OLT (p < 0.001) to be associated with the development of ESRD. The development of ESRD did not decrease patient survival (p = 0.111). ESRD patients who received subsequent kidney transplantation had significantly improved survival rates (p = 0.005). CONCLUSIONS: Serum creatinine levels at 1 yr, cyclosporine as immunosuppression, and the presence of diabetes pre-OLT are independent predictive factors for the development of ESRD. ESRD patients who received kidney transplantation had higher 10-yr survival rates when compared with patients maintained on dialysis.
Acute Kidney Injury↗
CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential.
CD4+ CD25+ regulatory T cells (Treg) are potent suppressors, and play important roles in autoimmunity and transplantation. Recent reports suggest that CD4+ CD25+ Treg are not a homogeneous cell population, but the differences in phenotype, function, and mechanisms among different subsets are unknown. Here, we demonstrate CD4+ CD25+ Treg cells can be divided into subsets according to cell-surface expression of CD62L. While both subsets express foxp3 and are anergic, the CD62L+ population is more potent on a per cell basis, and proliferates and maintains suppressive function far better than the CD62L- population and unseparated CD4+ CD25+ Treg. The CD62L+ population preferentially migrates to CCL19, MCP-1 and FTY720. Both CD62L+ and CD62L- subsets prevent the development of autoimmune gastritis and colitis induced by CD4+ CD25-CD45RBhigh cells in severe combined immunodeficiency (SCID) mice. Overall, these results suggest CD4+ CD25+ Treg are not a homogenous cell population, but can be divided into at least two subsets according to CD62L expression. The CD62L+ subset is a more potent suppressor than the CD62L- population or unfractionated CD4+ CD25+ Treg cells, can be expanded far more easily in culture, and is more responsive to chemokine-driven migration to secondary lymphoid organs. These properties may have significant implications for the clinical manipulation of the CD4+ CD25+ CD62L+ cells.
Animals↗
Decreased incidence of cytomegalovirus infection in thymoglobulin-treated transplant patients with 6 months of valganciclovir prophylaxis.
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Adult↗
Differential expression of chemokines and chemokine receptors in murine islet allografts: the role of CCR2 and CCR5 signaling pathways.
Chemokines and their receptors play a pivotal role in the initiation and amplification of the immune response. Investigated was their differential expression after syngeneic and allogeneic islet transplantation. During the 7 d after transplantation, the chemokines MCP-1, MCP-2, RANTES, MIG, IP-10, I-TAC, and two CC chemokine receptors CCR2 and CCR5 were highly expressed in allografts when compared with isografts. Disrupting the CCR2 and CCR5 pathways individually resulted in prolongation of the survival time 16.1 +/- 0.4 and 15.8 +/- 0.9 d, respectively, of fully major histocompatibility complex-mismatched islet grafts compared with wild-type controls (11.2 +/- 1.0 d). Blockade of both receptors had no synergistic effect. Rapamycin-treated wild-type recipients rejected their grafts at 17.4 +/- 2.2 d, in contrast to rapamycin-treated CCR2-/- recipients at 38 +/- 8.6 d (P = 0.025). The disruption of the CCR2 and CCR5 signaling, alone or in combination, moderately prolong islet allograft survival. However, the combination of low-dose immunosuppression and targeting of CCR2 greatly augmented islet graft survival.
Animals↗
Rapid steroid withdrawal in hepatitis C virus-positive kidney transplant recipients.
The effects of rapid steroid withdrawal (SW) on kidney transplantation (KT) outcome were investigated in 12 HCV+ patients in a prospective cohort study. These results were compared with 17 HCV+ patients who received KT in the prior 2 yr and treated with a standard prednisone taper protocol. SW patients received only 6 d of steroid treatment after transplantation. Eleven received Thymoglobulin and one Basiliximab induction treatment along with a calcineurin inhibitor and mycophenolate mofetil. Patient and graft survival was 92% in SW group (median follow-up 12 months, range 6-17), and 92 and 82% in the historic control group respectively (median follow-up 21 months, range 11-27). In the SW and control group, acute rejection rates were 9 and 18%, and mean creatinine levels at last follow-up 1.30 +/- 0.36 and 1.68 +/- 0.58 mg/dL respectively. Only two SW patients had an increase in liver function tests during follow-up (18%), compared with six patients in the control group (43%). This study demonstrates that rapid SW is safe for HCV+ KT recipients, without an increase in acute rejection episodes or liver function abnormalities in the short term.
Adult↗
TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 - precursors.
CD4 + CD25 + regulatory T cells (Tregs) are potent suppressors, playing important roles in autoimmunity and transplantation tolerance. Understanding the signals necessary for the generation and expansion of Tregs is important for clinical cellular therapy, but only limited progress has been made. Recent reports suggest a role for TGF-beta in the generation of Tregs from CD4 + CD25 - precursors, but the mechanism remains unknown. Here, we demonstrate that TGF-beta2 triggers Foxp3 expression in CD4 + CD25 - precursors, and these Foxp3 + cells act like conventional Tregs. The generation of Foxp3 + Tregs requires stimulation of the T-cell receptor, the IL-2R and the TGF-beta receptor. More importantly, strong costimulation through CD28 prevents Foxp3 expression and suppressive function in an IL-4-dependent manner. Furthermore, TGF-beta-driven Tregs inhibit innate inflammatory responses to syngeneic transplanted pancreatic islets and enhance islet transplant survival. Thus, TGF-beta is a key regulator of the signaling pathways that initiate and maintain Foxp3 expression and suppressive function in CD4 + CD25 - precursors. TGF-beta and signaling through TGF-beta receptor, CD28 costimulation and IL-4 may be key components for the manipulation of Treg. The de novo generation of Foxp3 + cells from CD4 + cells has the potential to be used for treatment of autoimmune diseases and induction of transplant tolerance.
Animals↗
Committing embryonic stem cells to early endocrine pancreas in vitro.
A panel of genetic markers was used to assess the in vitro commitment of murine embryonic stem (ES) cells toward the endoderm-derived pancreas and to distinguish insulin-expressing cells of this lineage from other lineages such as neuron, liver, and yolk sac. There are two nonallelic insulin genes in mice. Neuronal cells express only insulin II, whereas the pancreas expresses both insulin I and II. Yolk sac and fetal liver express predominately insulin II, small amounts of insulin I, and no glucagon. We found that ES-derived embryoid bodies cultured in the presence of stage-specific concentrations of monothio-glycerol and 15% fetal calf serum, followed by serum-free conditions, give rise to a population that expresses insulin I, insulin II, pdx-1 (a pancreas marker), and Sox17 (an endoderm marker). Immunohistochemical staining shows intracellular insulin particles, and its de novo production was confirmed by staining for C-peptide. Most, but not all, of the insulin+ or C-peptide+ cells coexpress glucagon, demonstrating a differentiation pathway to pancreas rather than yolk sac or fetal liver. Addition of beta-cell specification and differentiation factors activin beta B, nicotinamide, and exendin-4 to later-stage culture increased insulin-positive cells to 2.73% of the total population, compared with the control culture, which gave rise to less than 1% insulin-staining cells. These findings suggest that stepwise culture manipulations can direct ES cells to become early endocrine pancreas.
Animals↗
Intravenous immunoglobulin and thymoglobulin facilitate kidney transplantation in complement-dependent cytotoxicity B-cell and flow cytometry T- or B-cell crossmatch-positive patients.
BACKGROUND: The aim of this study was to investigate the effect of Thymoglobulin and intravenous immunoglobulin (i.v.IG) therapy on the clinical outcome of a putatively high-risk group of kidney transplant recipients who have positive B-cell complement-dependent cytotoxicity (CDC) along with positive T- or B-cell flow cytometry (FC) crossmatch results. METHODS: We prospectively studied the effects of i.v.IG and Thymoglobulin induction treatment in B-cell CDC, and T- or B-cell FC crossmatch-positive kidney transplant recipients (seven women and one man; mean age, 43+/-12 years). RESULTS: Mean peak panel-reactive antibody (PRA) was 47+/-32. Three patients had donor-specific antibody by flow PRA (two anti-DR4 and one anti-A2). Each recipient received induction treatment with i.v.IG 100 mg/kg for 3 days and Thymoglobulin 1.5 mg/kg for 5 days after transplantation. No acute cellular rejections occurred during a median follow-up of 15 months (range, 12-17 months). Only one acute humoral rejection occurred 8 days after transplantation, which responded to plasmapheresis, i.v.IG, and rituximab. One allograft was lost because of polyoma nephritis. Patient survival was 100% and allograft survival was 88%. CONCLUSION: Our results indicate that i.v.IG and Thymoglobulin induction treatment may facilitate kidney transplantation in B-cell CDC and T- or B-cell FC crossmatch-positive patients.
Adult↗
Leukotrienes, sphingolipids, and leukocyte trafficking.
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Animals↗
Suppressor of cytokine signaling 1 inhibits IL-10-mediated immune responses.
IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse CD4(+) T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-gamma resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-gamma signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCS1 and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-gamma signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-gamma signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms.
Animals↗
Orthotopic tracheal allografts undergo reepithelialization with recipient-derived epithelium.
BACKGROUND: While the rejection of heterotopic tracheal allografts is characterized by complete airway obliteration, the rejection of orthotopic allografts leads to airway edema and cellular infiltrate of the lamina propria, but is not associated with obliteration. We hypothesized that orthotopic tracheal allografts undergo reepithelialization with recipient-derived mucosa and that this process prevents airway obliteration. METHODS: Thirty mice were randomly assigned to 6 experimental groups. BALB/c donor tracheal segments were transplanted orthotopically or heterotopically into syngeneic BALB/c or major histocompatability mismatched allogeneic C57BL/6 recipients. Recipients of allogeneic grafts were divided into a nonimmunosuppression group and an immunosuppression group (cyclosporine, 7 mg/kg per day). Twenty-one days after transplantation, histological assessment, immunohistochemistry for CD4 and CD8 lymphocyte infiltration and major histocompatibility-specific immunohistochemistry were performed on the grafts to assess rejection and donor or recipient origin of tissue. RESULTS: Untreated heterotopic allografts underwent complete airway obliteration by day 21. This response was prevented with cyclosporine immunosuppression. Untreated orthotopic allografts, however, demonstrated edema and lymphocytic infiltrate of the lamina propria resulting in clinical stridor without airway obliteration. Immunosuppressed orthotopic allografts did not develop edema or infiltrate of the lamina propria and consequently stridor did not occur. Immunohistochemical analysis demonstrated migration of recipient-derived mucosa into the donor allograft segment in both the untreated and treated orthotopic groups. CONCLUSIONS: Airway obliteration characteristic of rejecting heterotopic tracheal allografts does not occur in the orthotopic allografts. Migration of recipient mucosa into the donor allograft appears to prevent airway obliteration in the orthotopic allografts. These findings suggest that the orthotopic tracheal transplantation model more accurately represents the biological behavior of clinical tracheal allografts than the traditional heterotopic model.
Airway Obstruction↗