Biomedical subjects

M D Griffin

Publications and source records attributed to M D Griffin.

At least 19 recordsLinked to original sources

PubMed2006

Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus.

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMF-prednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 +/- 19 mL/min vs. 63 +/- 18 mL/min, p = 0.57) or 2 years (61 +/- 17 mL/min vs. 61 +/- 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.

Adult↗

PubMed2006

Kidney transplant function and histological clearance of virus following diagnosis of polyomavirus-associated nephropathy (PVAN).

Polyomavirus-associated nephropathy (PVAN) is managed by reduced immunosuppression with or without antiviral therapy. Data from 55 patients with biopsy-proven PVAN were analyzed for adverse outcomes and influence of baseline variables and interventions. During 20+/-11 months follow-up, the frequencies of graft loss, major and any functional decline were 15%, 24% and 38%, respectively. Repeat biopsies were performed in 45 patients with persistent PVAN in 47%. Low-dose cidofovir, IVIG and cyclosporine conversion were used in 55%, 20% and 55% of patients. No single intervention was associated with improved outcome. Of the variables examined, only degree of interstitial fibrosis at diagnosis was associated with kidney function decline. In contrast, donor source, interstitial fibrosis, proportion of BKV positive tubules and plasma viral load at diagnosis were all associated with failure of histological viral clearance. This retrospective, nonrandomized analysis suggests that: (i) Graft loss within 2 years of PVAN diagnosis is now uncommon, but ongoing functional decline and persistent infection occur frequently. (ii) Low-dose cidofovir, IVIG and conversion to cyclosporine do not abrogate adverse outcomes following diagnosis. (iii) Fibrosis at the time of diagnosis predicts subsequent functional decline. Further elucidation of the natural history of PVAN and its response to individual interventions will require prospective clinical trials.

Adult↗

PubMed2001

Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

BACKGROUND: Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. METHODS: Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. RESULTS: The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. CONCLUSIONS: Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Adult↗

PubMed2001

The effects of CTLA-4Ig on acute lung allograft rejection: a comparison of intrabronchial gene therapy with systemic administration of protein.

BACKGROUND: Blockade of T-cell costimulation by local delivery of an adenoviral vector encoding for CTLA-4Ig and systemic administration of the protein are compared in a rat lung allograft model. METHODS: Left lungs of Brown Norway rats (RT1n) were transplanted into Lewis (RT11) recipients in four groups of six animals each: 1) no treatment; 2) intrabronchial transduction of donor lung with adenovirus encoding mCTLA-4Ig (adeno-mCTLA-4Ig); 3) intrabronchial transduction with empty adenovirus; and 4) intraperitoneal injection of mCTLA-4Ig. Grading of rejection, mCTLA-4Ig measurement in serum and bronchial washings, RT-PCR for virally encoded transcripts, and immunohistochemistry for mCTLA-4Ig were carried out 4 days later. RESULTS: Intrabronchial transduction with adeno-mCTLA-4Ig resulted in detectable transgene expression in graft tissue and bronchial fluid but not in serum. Significant reduction in rejection grade (from grade 3 to 2) occurred after systemic mCTLA-4Ig but not adeno-mCTLA-4Ig transduction. CONCLUSION: Local expression of immunomodulatory proteins can be achieved within lung allografts by intrabronchial delivery of adenoviral vector but may not significantly modify acute rejection.

Abatacept↗

PubMed2001

Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo.

Dendritic cells (DCs) play a central role in regulating immune activation and responses to self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of DCs is inhibited by physiological levels of 1alpha,25 dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and a related analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D(3) (D(3) analog). Conditioning of bone marrow cultures with 10(-10) M D(3) analog resulted in accumulation of immature DCs with reduced IL-12 secretion and without induction of transforming growth factor beta1. These DCs retained an immature phenotype after withdrawal of D(3) analog and exhibited blunted responses to maturing stimuli (CD40 ligation, macrophage products, or lipopolysaccharide). Resistance to maturation depended on the presence of the 1alpha,25(OH)(2)D(3) receptor (VDR). In an in vivo model of DC-mediated antigen-specific sensitization, D(3) analog-conditioned DCs failed to sensitize and, instead, promoted prolonged survival of subsequent skin grafts expressing the same antigen. To investigate the physiologic significance of 1alpha,25(OH)(2)D(3)/VDR-mediated modulation of DC maturity we analyzed DC populations from mice lacking VDR. Compared with wild-type animals, VDR-deficient mice had hypertrophy of subcutaneous lymph nodes and an increase in mature DCs in lymph nodes but not spleen. We conclude that 1alpha,25(OH)(2)D(3)/VDR mediates physiologically relevant inhibition of DC maturity that is resistant to maturational stimuli and modulates antigen-specific immune responses in vivo.

Animals↗

PubMed2001

Development and applications of surface-linked single chain antibodies against T-cell antigens.

In this report the use of surface-linkage to expand the potential experimental and therapeutic applications of single chain antibody (scFv) constructs is reviewed. A strategy for the generation and functional characterization of surface-linked scFvs that bind selectively to the T-cell proteins CD3epsilon, CD28, and CD152 (CTLA-4) is described in detail. Experimental examples are provided of the use of these constructs to study the positive and negative regulation of T-cell activation and to manipulate the in vivo immunogenicity of tumor cells. In addition, a novel system for Simultaneous T-cell Activation and Retroviral Transduction (START) is described in which retroviral packaging cells are rendered mitogenic for T lymphocytes by combined expression of surface-linked scFvs. Finally, the use of random mutagenesis and yeast surface display to increase the affinity and functional efficacy of scFv constructs is demonstrated.

Abatacept↗

PubMed2000

Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152).

CTLA-4 (CD152) engagement can down-regulate T cell activation and promote the induction of immune tolerance. However, the strategy of attenuating T cell activation by engaging CTLA-4 has been limited by sharing of its natural ligands with the costimulatory protein CD28. In the present study, a CTLA-4-specific single-chain Ab (scFv) was developed and expressed on the cell surface to promote selective engagement of this regulatory molecule. Transfectants expressing anti-CTLA-4 scFv at their surface bound soluble CTLA-4 but not soluble CD28. Coexpression of anti-CTLA-4 scFv with anti-CD3epsilon and anti-CD28 scFvs on artificial APCs reduced the proliferation and IL-2 production by resting and preactivated bulk T cells as well as CD4+ and CD8+ T cell subsets. Importantly, expression of anti-CTLA-4 scFv on the same cell surface as the TCR ligand was essential for the inhibitory effects of CTLA-4-specific ligation. CTLA-4-mediated inhibition of tyrosine phosphorylation of components of the proximal TCR signaling apparatus was similarly dependent on coexpression of TCR and CTLA-4 ligands on the same surface. These findings support a predominant role for CTLA-4 function in the modification of the proximal TCR signal. Using T cells from DO11.10 and 2C TCR transgenic mice, negative regulatory effects of selective CTLA-4 ligation were also demonstrated during the stimulation of Ag-specific CD4+ and CD8+ T cells by MHC/peptide complexes. Together these studies demonstrate that selective ligation of CTLA-4 using a membrane-bound scFv results in attenuated T cell responses only when coengaged with the TCR during T cell/APC interaction and define an approach to harnessing the immunomodulatory potential of CTLA-4-specific ligation.

Abatacept↗

PubMed2000

Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs.

We show that the immunosuppressive effects of 1alpha, 25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) are due, in part, to inhibition of the T cell stimulatory functions of dendritic cells (DCs). Addition of 10(-12) and 10(-8) M 1alpha,25(OH)(2)D(3) to murine DC cultures resulted in a concentration-dependent reduction in levels of class II MHC and the co-stimulatory ligands B7-1, B7-2, and CD40 without affecting the number of DCs generated. Higher concentrations of 1alpha,25(OH)(2)D(3) reduced DC yield. The capacity of DCs to induce proliferation of purified allogeneic T cells was reduced by 1alpha,25(OH)(2)D(3). The vitamin D(3) analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor -D(3), exerted identical effects at 100-fold lower concentrations. Inhibition of DC maturation and stimulatory function was absent in cultures from mice genetically lacking vitamin D receptors (VDR). Vitamin D analogs effectively reduce DC function via VDR-dependent pathways.

Animals↗

PubMed1999

Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses.

Mice lacking CTLA-4 die at an age of 2-3 wk due to massive lymphoproliferation, leading to lymphocytic infiltration and destruction of major organs. The onset of the lymphoproliferative disease can be delayed by treatment with murine CTLA4Ig (mCTLA4Ig), starting day 12 after birth. In this study, we have characterized the T cells present in CTLA-4-deficient mice before and after mCTLA4Ig treatment. The T cells present in CTLA-4-deficient mice express the activation markers, CD69 and IL-2R; down-regulate the lymphoid homing receptor, CD62L; proliferate spontaneously in vitro and cannot be costimulated with anti-CD28 mAb consistent with a hyperactivated state. The T cells from CTLA-4-deficient mice survive longer in culture correlating with higher expression of the survival factor, Bcl-xL, in these cells. Most significantly, the CD4+ T cell subset present in CTLA-4-deficient mice secretes high levels of IL-4 and IL-5 upon TCR activation. Treatment of CTLA-4-deficient mice treated with mCTLA4Ig reverses the activation and hyperproliferative phenotype of the CTLA-4-deficient T cells and restores the costimulatory activity of anti-CD28 mAb. Furthermore, T cells from mCTLA4Ig-treated mice are not skewed toward a Th2 cytokine phenotype. Thus, CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells. This process results in apoptosis-resistant, CD4+ T cells with a predominantly Th2 phenotype that may be involved in the lethal phenotype in these animals.

Abatacept↗

PubMed1998

Prolonged anuria complicating primary sclerosing cholangitis: successful outcome following orthotopic liver transplantation.

A 49-year-old man with progressive obstructive jaundice secondary to primary sclerosing cholangitis developed acute, anuric renal failure requiring prolonged hemodialysis. Renal biopsy showed evidence of tubular epithelial toxicity, pigmented casts, interstitial fibrosis, and ischemic glomerular changes. After orthotopic liver transplantation (OLT), there was an immediate return of urine output. The introduction of tacrolimus (FK506) was delayed for 3 weeks after transplantation, during which time a gradual improvement in renal function occurred. Renal function remained stable 1 year later at a level of moderate impairment with good hepatic function.

Acute Kidney Injury↗

PubMed1997

Expression of polycystin in mouse metanephros and extra-metanephric tissues.

The presence of messenger RNA for the mouse homologue of the polycystic kidney disease 1 gene (PKD1) was demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) methods in mouse embryo messenger RNA. A single locus for the PKD1 gene was detected on mouse chromosome 17 by fluorescent in situ hybridization. Immunoprecipitation of proteins from [35S] methionine-labeled mouse metanephric explants with an anti-polycystin antibody (Pc1) revealed high molecular weight bands, the highest being > 400 kDa. Immunoperoxidase staining of mouse embryos with Pc1 revealed expression of polycystin as early as day 8 gestation. The expression was seen in epithelial cells of the ureteric bud, in condensing blastemal cells of the developing metanephros and, subsequently, in cells of the nascent tubules. In addition, Pc1 immunoreactivity was seen in hepatocytes and biliary epithelium, cardiac and skeletal muscle, neural tissue, gut, and bronchial epithelium. In post-natal and adult mouse kidney and liver persistent slight to moderate immunoreactivity was observed. Immunofluorescent studies of cultured 13-day mouse metanephroi revealed polycystin expression in ureteric bud epithelium, early glomerular structures (that is, condensates, S-shaped and comma-shaped bodies) and in proximal and distal tubular epithelia. These data indicate that the mouse has a single gene homologous to human PKD1 on chromosome 17, and polycystin is expressed in a variety of tissues during embryonic development.

Age Factors↗

PubMed1997

Neonatal presentation of autosomal dominant polycystic kidney disease with a maternal history of tuberous sclerosis.

BACKGROUND: Childhood presentation of polycystic kidney disease has been reported with tuberous sclerosis complex (TSC). Recently some such cases have been shown to be due to combined deletion of the PKD1 and TSC2 genes, which lie close together on chromosome 16. The phenomenon of anticipation, whereby disease presentation occurs at a progressively earlier age in each generation, has been suggested to occur in autosomal dominant polycystic kidney disease (ADPKD). We have carried out a genetic study of a family in which these issues became clinically relevant. Neonatal presentation of polycystic kidneys occurred in an individual with a maternal family history of epilepsy and features of TSC without renal cystic disease. METHODS: Detailed historical and clinical profiles were gathered for three generations of the maternal and paternal families. Both parents underwent renal ultrasound scanning. Genomic DNA was obtained from affected and unaffected individuals from the maternal family and used for linkage analysis to gene loci for TSC. RESULTS: Renal cysts were not present in the mother by ultrasound. Linkage to TSC2 was found for members of the maternal family with clinical features of TSC. While a diagnosis of TSC was confirmed in her mother the child was found not to have inherited the disease-related allele. The father was found to have asymptomatic bilateral polycystic kidneys consistent with ADPKD. The presence of ADPKD in other paternal relatives could not be confirmed. CONCLUSIONS: The index case was found to have paternally inherited ADPKD with unusually early presentation. While at risk for concomitant maternal inheritance of TSC this diagnosis was ruled out by linkage analysis studies. The ability to clarify the true nature of a complex inherited condition greatly facilitates future management and counselling. The mechanisms underlying phenotypic heterogeneity in ADPKD remain to be clearly defined and are the subject of ongoing investigation.

Female↗

PubMed1997

Cystic kidney diseases.

The goal of understanding the primary defects that lead to renal cystic diseases has proved to be an elusive one, despite 3 decades of physiologic and genetic investigation. Within the past 2 years the genes responsible for type 1 and type 2 autosomal dominant polycystic kidney disease have been identified. The process of defining the normal distribution and functions of the proteins encoded by these genes as well as the precise pathophysiology of cystogenesis is underway. For other major hereditary cystic kidney diseases, chromosomal localization or gene identification has also been achieved in recent years. Mouse and rat models of renal cystic disease continue to be a rich source of new data on the effect of genetic and environmental modifying factors on disease progression as well as serving as a preliminary testing ground for novel approaches to management such as gene therapy and early dietary modification. Ongoing clinical research continues to better define the renal and extra-renal manifestations of autosomal dominant polycystic and other renal cystic diseases. It is likely that a clearer understanding of the pathophysiology of these diseases will provide important insights into the processes that control tissue development and growth, and cellular differentiation.

Animals↗

PubMed1997

Diffuse proliferative glomerulonephritis and acute renal failure associated with acute staphylococcal osteomyelitis.

A 72-year-old man developed acute renal failure after coronary bypass surgery that had been complicated by sternal osteomyelitis caused by the Staphylococcus aureus bacterium. Bacteremia and sepsis were not present. Renal biopsy demonstrated a florid, diffuse, proliferative glomerulonephritis with glomerular immune complex deposition. Management included hemodialysis, prolonged antibiotic therapy, and repeated surgical debridement. Spontaneous recovery of renal function occurred after eradication of infection and final surgical wound repair. The relationship between acute bacterial infections and glomerulonephritis and, in particular, the causal role of staphylococcal antigens in the pathogenesis of such lesions is discussed.

Acute Kidney Injury↗

PubMed1997

Vascular expression of polycystin.

Autosomal dominant polycystic kidney disease (AD-PKD) is predominantly caused by mutations of the gene PKD1, which encodes a large protein, polycystin, of unknown function. A variety of arterial abnormalities occur with increased prevalence in ADPKD patients. Using an antiserum against the nonduplicated region of the polycystin protein, immunostaining of vascular smooth muscle cells was detected in normal adult elastic arteries. Partial digestion of tissue slices with nonspecific proteases greatly enhanced this staining. Similar enhancement was seen with specific elastase digestion. Immunostaining for smooth muscle actin was not affected by elastase. Antiserum preadsorbed with peptide antigen gave no staining. In specimens of intracranial aneurysms, aortic dissections, and dolichoectatic arteries from thirteen patients with ADPKD, immunostaining of variable intensity for polycystin was demonstrated in arterial smooth muscle cells and myofibroblasts, along with disruption of elastic laminae. Further elastase digestion did not significantly alter staining patterns. Intracranial aneurysms from patients without ADPKD also showed a variable degree of immunostaining with polycystin antisera in the same distribution. The expression of polycystin in arterial smooth muscle suggests a direct pathogenic role for ADPKD-related mutations in the arterial complications of this disease.

Adolescent↗

PubMed1997

Swanson metacarpophalangeal joint arthroplasty in patients with rheumatoid arthritis.

Between 1981 and 1991, 348 Swanson metacarpophalangeal replacements were implanted in patients with rheumatoid arthritis. There were 64 female and seven male patients. Both hands were reconstructed in 18 patients. Clinically, 170 implants were available for an average of 5.2 years (range, 2-10 years) followup. Severe synovitis was seen in 7% of metacarpophalangeal joints, moderate synovitis in 25%, slight synovitis in 17%, and synovitis was not present in 51%. Pain was found to be severe in 4% of the joints, moderate in 3%, slight in 39%, and not present in 54% of the joints. The average preoperative active arc of motion was 38 degrees, and the average postoperative arc of motion was 27 degrees. Eleven of 12 fractures found were revised. There were no infections. Functionally, of 58 patients assessed, 58 (100%) reported the ability to feed themselves, 55 (94%) to button clothes, and 54 (93%) to write. Quality radiographs were available in 144 joints. Eighty-four percent of implants showed sclerosis of bone and 8% showed resorption adjacent to the implant. Survivorship analysis revealed a 94% success rate at 5 years, 93% at 7 years, and 90% at 10 years using the end point of revision surgery.

Arthritis, Rheumatoid↗

PubMed1996

Immunolocalization of polycystin in human tissues and cultured cells.

The gene PKD I, which is mutated in type I autosomal dominant polycystic kidney disease (ADPKD 1), encodes a large protein of novel structure and unknown function and distribution that has been named polycystin. To gain better insight into polycystin function, we raised a panel of antisera against synthetic peptide antigens derived from the unique portion of the predicted polycystin sequence. Antisera were used to immunolocalize the protein in a variety of normal human fetal, childhood, and adult tissues as well as kidney and liver tissue from individuals with ADPKD 1, the genetically distinct ADPKD 2, and acquired renal cystic disease (ARCD). Subcellular localization studies were carried out on human cultured cell lines of renal epithelial origin. In normal tissues, polycystin expression was noted in renal tubular epithelial cells from 20 weeks gestation to 4 years postpartum, and in hepatocytes and biliary epithelium up to 4 years, but not in adult kidney or liver. Expression also was present in fetal and childhood pancreas, myocardium, bowel, and adrenal medulla. In cell lines of renal epithelial origin, immunofluorescence and immunoelectron-microscopical studies showed localization of polycystin epitopes to the peripheral cytoplasm. Kidney and liver from four unrelated adults with known ADPKD 1 showed strong staining, which was not seen in kidney and liver from one adult with ADPKD 2 or in kidney from three patients with ARCD. We conclude that polycystin is expressed in renal tubular epithelial cells as well as a variety of other cell types during development and growth but is absent or weakly expressed in adult kidney and liver. Overexpression of polycystin epitopes within affected tissue may be a specific feature of some or all cases of ADPKD 1.

Adult↗

PubMed1995

Renal papillary necrosis--a sixteen-year clinical experience.

This study sought to characterize patients with renal papillary necrosis seen at one tertiary referral center by reviewing medical records of patients with a confirmed diagnosis between January 1, 1976 and September 1, 1992. One hundred sixty-five cases were identified. The mean age at diagnosis was 57 yr (SD 15). The female-to-male ratio was 1.1:1.0. Ninety-two percent of patients were white. Seventy-seven percent of cases were unsuspected before diagnosis, and 16% were diagnosed at autopsy. The most common associated conditions were urinary tract infection, analgesic abuse, urinary tract obstruction, diabetes mellitus, and sickle cell disease. There was considerable overlap in the presence of these conditions, with two or more identified in 36% of patients. In addition, 11% of patients had none of these well-recognized risks. Other diagnoses in this group included lupus nephritis, Wegener's granulomatosis, and renal artery stenosis. A decline in case numbers of approximately 50% was demonstrated over the last 10 yr studied. This period was associated with a 57% reduction in the number of excretory urograms carried out, suggesting that changes in diagnostic imaging preference may have contributed. Vital status and renal outcome data after diagnosis were obtained in 93% of cases. Of those diagnosed while living, survival was lowest among diabetic patients. Ten-year survival for nondiabetics was not significantly different from the expected survival of an age- and sex-matched cohort. The overall risk for requiring renal replacement therapy after the diagnosis of renal papillary necrosis in surviving patients was low (7% of 136 patients at risk).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗