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Biomedical subjects

C A Bonham

Publications and source records attributed to C A Bonham.

At least 19 recordsLinked to original sources
PubMed2001

Liver-derived DEC205+B220+CD19- dendritic cells regulate T cell responses.

Leukocytes resident in the liver may play a role in immune responses. We describe a cell population propagated from mouse liver nonparenchymal cells in IL-3 and anti-CD40 mAb that exhibits a distinct surface immunophenotype and function in directing differentiation of naive allogeneic T cells. After culture, such cells are DEC-205(bright)B220+CD11c-CD19-, and negative for T (CD3, CD4, CD8alpha), NK (NK 1.1) cell markers, and myeloid Ags (CD11b, CD13, CD14). These liver-derived DEC205+B220+ CD19- cells have a morphology and migratory capacity similar to dendritic cells. Interestingly, they possess Ig gene rearrangements, but lack Ig molecule expression on the cell surface. They induce low thymidine uptake of allogeneic T cells in MLR due to extensive apoptosis of activated T cells. T cell proliferation is restored by addition of the common caspase inhibitor peptide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk). T cells stimulated by liver-derived DEC205+B220+D19- cells release both IL-10 and IFN-gamma, small amounts of TGF-beta, and no IL-2 or IL-4, a cytokine profile resembling T regulatory type 1 cells. Expression of IL-10 and IFN-gamma, but not bioactive IL-12 in liver DEC205+B220+CD19- cells was demonstrated by RNase protection assay. In vivo administration of liver DEC205+B220+CD19- cells significantly prolonged the survival of vascularized cardiac allografts in an alloantigen-specific manner.

Animals↗
PubMed2000

Is the pathologic TNM staging system for patients with hepatoma predictive of outcome?

BACKGROUND: The pathologic TNM (pTNM) staging system was designed to aid in determining the prognosis of cancer patients and in planning and evaluating their treatment. The current pTNM classification system was not found to be predictive for patients undergoing orthotopic liver transplantation (OLTx) in the presence of hepatocellular carcinoma (HCC). Therefore, the authors examined the current system to determine whether improvements would allow the development of a more predictive system. METHODS: Three hundred seven patients with HCC underwent OLTx between 1981 and 1997. Risk factors for recurrence were identified using the Kaplan-Meier method with the log rank test. The Cox proportional hazards model was used to identify factors independently predictive of recurrence which were then used to create a new staging system. RESULTS: There was neither a direct correlation between the current pTNM system and tumor free survival nor homogeneity in outcomes for patients within certain current pTNM categories. Depth of vascular invasion, lobar distribution, lymph node status, and largest tumor size were found to be independent predictors of tumor free survival; tumor number was not found to be significant in multivariate analysis. A new staging system is proposed, which takes into account the results of the multivariate analysis in which tumor free survival correlates directly with stage. CONCLUSIONS: The proposed staging system is superior to the current pTNM staging system in predicting tumor free survival following OLTx with HCC. Further studies will determine the appropriateness of this system for staging HCC after subtotal hepatic resection.

Adolescent↗
PubMed2000

Prolongation of cardiac allograft survival using dendritic cells treated with NF-kB decoy oligodeoxyribonucleotides.

Dendritic cells (DC) classically promote immune responses but can be manipulated to induce antigen-specific hyporesponsiveness in vitro. The expression of costimulatory molecules (CD40, CD86, CD80) at the DC cell surface correlates with their capacity to induce or suppress immune responses. Expression of these molecules is associated with NF-kB-dependent transcription of their genes. DC tolerogenicity has been associated with impaired NF-kB-dependent transcription of costimulatory genes as well as NF-kB translocation to the nucleus. In this report, we demonstrate that double-stranded oligodeoxyribonucleotides containing binding sites for NF-kB (NF-kB ODN) are efficiently incorporated by bone marrow-derived DC and specifically inhibit NF-kB-dependent transcription of a reporter gene. Moreover, exposure of DC to the oligonucleotide decoys inhibited lipopolysaccharide (LPS)-induced nitric oxide production, a marker of DC maturation. Treatment of bone marrow-derived DC progenitors with NF-kB ODN selectively suppressed the cell-surface expression of costimulatory molecules without interfering with MHC class I or class II expression. Furthermore, NF-kB ODN DC induced allogeneic donor-specific hyporesponsiveness in mixed leukocyte cultures, and this was associated with inhibition of Th1-type cytokine production. Finally, infusion of NF-kB ODN-modified bone marrow-derived DC into allogeneic recipients prior to heart transplantation resulted in significant prolongation of allograft survival in the absence of immunosuppression. Specific interference with NF-kB and other transcriptional pathways involved in immune stimulation in DC using ODN decoy approaches could be one means to promote tolerance induction in organ transplantation.

Animals↗
PubMed2000

Lamivudine after hepatitis B immune globulin is effective in preventing hepatitis B recurrence after liver transplantation.

The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT.

Adult↗
PubMed2000

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center.

OBJECTIVE: To evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. SUMMARY BACKGROUND DATA: Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. METHODS: Four thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. RESULTS: The overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. CONCLUSION: Significantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

Adolescent↗
PubMed1999

Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors.

BACKGROUND: The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc+ donors in recipients who are susceptible to de novo hepatitis B virus (HBV) infection. The efficacy of hepatitis B immune globulin and lamivudine to prevent de novo HBV infection in anti-HBs negative recipients of allografts from anti-HBc+ donors has not been investigated. METHODS: After liver transplantation with an allograft from a donor positive for anti-HBc, recipients who were anti-HBs-, HbsAg- received hepatitis B immune globulin (HBIG) 10,000 IU i.v. daily for 7 days and monthly for 6 months. After 6 months, 1000 IU of HBIG was given IM. every 2 weeks for 18 months. Patients transplanted after 4/1/97 were given lamivudine 150 mg daily starting postoperative day 1. RESULTS: Between 8/14/96 and 6/10/98, 264 orthotopic liver transplants were performed and 16 anti-HBs-, HbsAg- patients received an hepatic allograft from a donor positive for anti-HBc. HBIG mono-therapy was administered to one patient. HBIG and lamivudine combination therapy was administered to 15 patients. Of the 16 patients, 8 were positive only for anti-HBc before transplant, and 8 were naive (anti-HBs-, anti-HBc-). The single patient who received HBIG monotherapy became HbsAg+ at 6 months. All patients receiving combination therapy with HBIG and lamivudine have remained HbsAg-. The average follow-up is 459 days (range 170-754). Two patients died from unrelated causes. CONCLUSIONS: Combination therapy with HBIG and lamivudine may prevent de novo HBV infection in anti-HBs-, HbsAg- recipients of hepatic allografts from anti-HBc+ donors.

Hepatitis B↗
PubMed1999

Strategies to expand the donor pool for pancreas transplantation.

BACKGROUND: Our organ procurement organization has been forced to liberalize the donor criteria in order to expand the donor pool for pancreas transplantation. In this report, we describe our experience using whole organ pancreatic grafts from "marginal" donors, which include grafts obtained from donors over 45 years of age and from donors who were identified to be hemodynamically unstable at the time of organ retrieval. METHODS: A prospective study was performed between July 1994 and March 1998, during which time 137 pancreas transplants were performed at our center using organs procured by our own surgeons (organs sent by other teams were excluded). The rapid en bloc technique was used exclusively. The use of pancreatic grafts from marginal donors was analyzed for short-term and overall graft survival, and for delayed graft function and complications. RESULTS: Overall pancreas graft survival for our series was 83%, with a mean follow-up of 23 months. There were 22 pancreas grafts from donors over 45 years of age, 13 of whom were greater than 50 years of age. The actual graft survival rate of the over-45 donor group was 86%. Fifty-one grafts were removed from hemodynamically unstable donors on high-dose vasopressors. The actual graft survival in this group was 86%. There was no significant difference found in graft survival between recipients of pancreatic grafts from marginal and nonmarginal donors. Delayed graft function was exhibited by more recipients of grafts from donors on high-dose vasopressors (P<0.05), but this had no effect on long-term graft survival and endocrine function. Recipients of marginal donor grafts did not have higher rates of complication compared to recipients of nonmarginal grafts. CONCLUSIONS: Based on our results, we currently employ a graft selection strategy not limited by donor age or hemodynamic stability. Our selection of pancreas organs for transplantation is based on careful inspection of the pancreas and determination of the adequacy of the ex vivo flush. Our results suggest that the current pancreas donor pool may be expanded substantially.

Adolescent↗
PubMed1999

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients.

Dendritic cells (DC) are highly specialized antigen-presenting cells (APC) that initiate and modulate immune responses. They are essential for naive T cell activation, but may also play roles both in central and peripheral tolerance. Blockade of costimulatory pathways that provide the crucial second signal for lymphocyte activation is one strategy to augment the potential tolerogenicity of DC. Here, in vitro propagated DC were transduced using an adenoviral (Ad) vector to express the gene encoding cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4lg), which blocks interaction of CD80 and CD86 on DC with CD28 on T cells. Supernatants of AdCTLA4lg-transduced DC strikingly inhibited mixed leukocyte reactions (MLR) induced by non-transduced DC. Whereas transduction of marker genes (LacZ or enhanced green fluorescence protein (EGFP)) did not alter their potent allostimulatory activity, DC transduced with CTLA4lg exhibited striking reductions in cell surface staining for CD86, but not MHC class II, and were poor stimulators of T cell proliferation and cytotoxic T lymphocyte (CTL) responses. In addition, they induced alloantigen-specific T cell hyporesponsiveness. They were detected, following local injection, in significantly increased numbers in the lymphoid tissue of unmodified allogeneic recipients. This is the first report of the functional properties of DC genetically engineered to express CTLA4lg.

Abatacept↗
PubMed1998

Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management.

BACKGROUND: Precise diagnosis of central nervous system (CNS) lesions in liver transplant recipients remains problematic. Brain biopsies are often not feasible as a result of coagulopathy. We sought to determine whether selected clinical or radiologic characteristics can predict the likely etiology of CNS lesions in liver transplant recipients and thus obviate the need for diagnostic brain biopsies. METHODS: A 4-year prospective, observational, cohort study was conducted at liver transplant centers at four geographically diverse medical institutions. A total of 1730 consecutive liver transplant recipients were evaluated for CNS lesions; 60 patients with radiologically documented CNS lesions comprised the study sample. RESULTS: Vascular events (52%, 31/60), infections (181%, 11/60), immunosuppressive associated leukoencephalopathy (12%, 7/60), central pontine myelinolysis (8%, 5/60), and malignancy (3%, 2/60) were the predominant etiologies of CNS lesions. CNS lesions were most likely to occur within 30 days of transplantation (43%, 26/60); central pontine myelinolysis, subdural hematoma, acute infarcts, and Aspergillus brain abscesses were the predominant etiologies during this time. All brain abscesses were fungal; 73% (8/11) of these patients concurrently had documented extraneural (pulmonary) infection as a result of the same fungal pathogen. Thus, a diagnostic brain biopsy is not warranted in these patients. Patients on dialysis were more likely to have ischemic or infectious CNS lesions (P=0.03). Vascular events were more likely to occur in repeat transplant recipients (P=0.03). Twenty-five percent (15/60) of the CNS lesions occurred more than 1 year after transplantation; small vessel ischemic lesions, malignancy, or non-Aspergillus fungal brain abscesses accounted for all such lesions. CONCLUSIONS: A presumptive etiologic diagnosis can be established in a vast majority of CNS lesions in liver transplant recipients based on identifiable presentation that includes time of onset, unique risk factors, and neuroimaging characteristics. Empiric therapy of brain abscesses in liver transplant recipients should include antifungal and not antibacterial agents.

Adult↗
PubMed1997

Striking augmentation of hematopoietic cell chimerism in noncytoablated allogeneic bone marrow recipients by FLT3 ligand and tacrolimus.

The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and the recently identified hematopoietic stem-progenitor cell mobilizing factor flt3 ligand (FL) on donor leukocyte microchimerism in noncytodepleted recipients of allogeneic bone marrow (BM) was compared. B10 mice (H2b) given 50x10(6) allogeneic (B10.BR [H2k]) BM cells also received either GM-CSF (4 microg/day s.c.), FL (10 microg/day i.p.), or no cytokine, with or without concomitant tacrolimus (formerly FK506; 2 mg/kg) from day 0. Chimerism was quantitated in the spleen 7 days after transplantation by both polymerase chain reaction (donor DNA [major histocompatibility complex class II; I-E(k)]) and immunohistochemical (donor [I-E(k)+] cell) analyses. Whereas GM-CSF alone significantly augmented (fivefold) the level of donor DNA in recipients' spleens, FL alone caused a significant (60%) reduction. Donor DNA was increased 10-fold by tacrolimus alone, whereas coadministration of GM-CSF and tacrolimus resulted in a greater than additive effect (28-fold increase). A much more striking effect was observed with FL + tacrolimus (>125-fold increase in donor DNA compared with BM alone). These findings were reflected in the relative numbers of donor major histocompatibility complex class II+ cells (many resembling dendritic cells) detected in spleens, although quantitative differences among the groups were less pronounced. Evaluation of cytotoxic T lymphocyte generation by BM recipients' spleen cells revealed that FL alone augmented antidonor immunity and that this was reversed by tacrolimus. Thus, although FL may potentiate antidonor reactivity in nonimmunosuppressed, allogeneic BM recipients, it exhibits potent chimerism-enhancing activity when coadministered with recipient immunosuppressive therapy.

Animals↗
PubMed1996

Nitric oxide production by mouse bone marrow-derived dendritic cells: implications for the regulation of allogeneic T cell responses.

Dendritic cells (DC) are the most potent known antigen presenting cells, and play important roles both in immunity and tolerance induction. Nitric oxide (NO) is an important effector molecule that is involved in numerous aspects of the immune response. There have been no accounts to date of efforts to determine NO generation by well-characterized DC. In this report we describe the production of NO by highly purified DEC 205+ DC propagated from mouse bone marrow in response to granulocyte/macrophage-colony stimulating factor (GM-CSF) + interleukin-4 (IL-4). NO synthesis was induced in DC by interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS), and was blocked by the inhibitor of nitric oxide synthase (NOS), NG-monomethyl-L-arginine (NMMA). Both "mature" B7-2+ (CD86+) DC and B7-2- (CD86-) DC progenitors could be induced to release NO. NO was also recovered from the supernatants of primary mixed leukocyte cultures containing comparatively high concentrations of B7-2+ DC in relation to purified allogeneic T cells. Furthermore, inhibition of NO release in these cultures by NMMA resulted in an increase in T cell proliferation. These observations suggest that NO may be an important soluble mediator of the interaction between DC and activated T cells. In addition to its ability to inhibit T cell proliferation, NO was also shown to induce programmed cell death in DC. This was visualized by the detection of DNA strand breaks with in situ nick translation. The percentage of DC apoptosis correlated with the level of NO in the cultures. Apoptosis was inhibited by the addition of NMMA. These results indicate that DC have the capacity both to stimulate and potentially limit the same allogeneic T cell response, in accordance with their production of NO.

Animals↗
PubMed1996

Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis.

Nitric oxide (NO) is an important effector molecule that is involved in immune regulation and host defense. In this study, highly purified NLDC 145+ (DEC-205+) MHC class II(bright) B7-2+ dendritic cells (DC) propagated from normal mouse bone marrow in response to granulocyte-macrophage CSF + IL-4 were induced to produce NO by IFN-gamma and LPS. NO production was inhibited by the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (NMMA). Nitrite also accumulated in mixed leukocyte culture supernatants as the result of coculture of DC with purified naive allogeneic T cells. Furthermore, NO production was induced by CD40 ligation. Suboptimal T cell proliferation observed at high relative concentrations of DC correlated with increased NO production and was mitigated by NMMA. Induction of mRNA for an inducible NOS (iNOS) in DC was confirmed by Northern blotting, whereas intracellular iNOS was visualized by two-color flow cytometry and by both immunofluorescent and immunogold labeling in a subpopulation of IFN-gamma + LPS-stimulated cells. Both endogenous NO production and exposure of unstimulated DC to the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) resulted in DC apoptosis. Thus, although DC function initially as the most potent APCs for T cell activation, DC induced to synthesize NOS by IFN-gamma may inhibit (allogeneic) T cell proliferation: NO may suppress lymphocyte proliferation and also induce apoptosis of the most potent source of alloantigenic stimulation.

Animals↗
PubMed1996

TGF-beta 1 pretreatment impairs the allostimulatory function of human bone marrow-derived antigen-presenting cells for both naive and primed T cells.

Transforming growth factor-beta (TGF-beta) exhibits strong antiproliferative effects upon lymphocytes and inhibits many of the effector functions of activated immune cells. However, its influence on the inductive phase of immune responses, and in particular its effect on antigen-presenting cells (APC), has not been well studied. In this investigation, we examined the influence of human TGF-beta 1 on the antigen-presenting function of human bone marrow (BM)-derived APC propagated in liquid culture for 11-17 days in response to granulocyte/macrophage colony-stimulating factor (GM-CSF). These cells were predominantly macrophages, accompanied by a minor population of dendritic cells. TGF-beta 1 had no effect upon the allostimulatory function of vertebral body whole BM cells cultured for 3-5 days in GM-CSF. However, it markedly reduced the allostimulatory capacity of BM-derived APC exposed to the cytokine for the last 3 days of culture. This inhibitory action could not be ascribed to cytokine 'carry-over', or to any consistent changes in the expression of cell surface molecules implicated in antigen presentation (HLA-DR), intercellular adhesion (ICAM-1; CD54), or costimulatory activity (B7-1; CD80). Mechanisms that may underlie the inhibitory action of TGF-beta on APC function and the immunologic and possible clinical implications of the findings are discussed.

Antigen-Presenting Cells↗