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Biomedical subjects

Roslyn B Mannon

Publications and source records attributed to Roslyn B Mannon.

At least 19 recordsLinked to original sources
PubMed2006

Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay.

BACKGROUND: Long-term use of immunosuppressants is associated with significant morbidity and mortality in transplant recipients. A simple whole blood assay that has U.S. Food and Drug Administration clearance directly assesses the net state of immune function of allograft recipients for better individualization of therapy. A meta-analysis of 504 solid organ transplant recipients (heart, kidney, kidney-pancreas, liver and small bowel) from 10 U.S. centers was performed using the Cylex ImmuKnow assay. METHODS: Blood samples were taken from recipients at various times posttransplant and compared with clinical course (stable, rejection, infection). In this analysis, 39 biopsy-proven cellular rejections and 66 diagnosed infections occurred. Odds ratios of infection or rejection were calculated based on measured immune response values. RESULTS: A recipient with an immune response value of 25 ng/ml adenosine triphosphate (ATP) was 12 times (95% confidence of 4 to 36) more likely to develop an infection than a recipient with a stronger immune response. Similarly, a recipient with an immune response of 700 ng/ml ATP was 30 times (95% confidence of 8 to 112) more likely to develop a cellular rejection than a recipient with a lower immune response value. Of note is the intersection of odds ratio curves for infection and rejection in the moderate immune response zone (280 ng/ml ATP). This intersection of risk curves provides an immunological target of immune function for solid organ recipients. CONCLUSION: These data show that the Cylex ImmuKnow assay has a high negative predictive value and provides a target immunological response zone for minimizing risk and managing patients to stability.

Graft Rejection↗
PubMed2006

Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154.

CD154 is a cell surface molecule expressed on activated T cells that binds to CD40, an activating molecule on APCs. Its blockade has been shown to prevent allograft rejection, presumably by interrupting interactions between T cells and APCs. It is known that activated human platelets express and shed CD154 and can induce APC activation and other immune processes in vitro. Here we show that platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of any cellular source of this molecule. CD154-KO mice reject cardiac allografts after receiving CD154-expressing human platelets or recombinant CD154 (rCD154) trimers. Treatment with the human CD154-specific mAb 5c8 specifically prevents this induced rejection. Soluble trimers, but not platelets, induce rejection when infused temporally remote from the surgical procedure, suggesting that surgically induced platelet activation is required for CD154 release. Allograft rejection can thus be instigated by activated platelets through CD154. These data implicate platelets as a proximal component of acquired alloimmunity, providing insight into the mechanisms of allograft rejection and the physiological response to trauma in general.

Animals↗
PubMed2005

Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin.

BACKGROUND: Perioperative lymphocyte depletion induces allograft tolerance in some animal models, but in humans has only been shown to reduce immunosuppressive requirements. Without maintenance immunosuppression, depleted human renal allograft recipients experience rejection characterized by infiltration of the allograft with monocytes and macrophages. T-cell depletion combined with a brief course of deoxyspergualin (DSG), a drug with inhibitory effects on monocytes and macrophages, induces tolerance in nonhuman primates. We therefore performed a trial to determine if lymphocyte depletion with alemtuzumab combined with DSG would induce tolerance in humans. METHODS: Five recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction. Results were compared to previously studied patients receiving alemtuzumab alone or standard immunosuppression. RESULTS: Despite profound T-cell depletion and therapeutic DSG dosing, all alemtuzumab/DSG patients developed reversible rejection that was similar in timing, histology, and transcriptional profile to that seen in patients treated with alemtuzumab alone. Chemokine expression was marked prior to and during rejections. CONCLUSIONS: We conclude that treatment with alemtuzumab and DSG does not induce tolerance in humans. Chemokine production may not be adequately suppressed using this approach.

Adult↗
PubMed2005

Detection and localization of proteinuria by dynamic contrast-enhanced magnetic resonance imaging using MS325.

After renal transplantation, persistent glomerular disease affecting the native kidneys typically causes albuminuria, at least for a period of time, making it difficult to determine in a noninvasive fashion whether proteinuria originates in the native kidneys or the renal allograft. To address this problem, dynamic contrast-enhanced magnetic resonance imaging (MRI) using gadolinium (Gd)-based albumin-bound blood pool contrast agent (MS325) to localize proteinuria was investigated. Glomerular proteinuria was induced in Sprague-Dawley rats by intravenous injection of puromycin aminonucleoside (PAN), whereas control rats received physiologic saline vehicle. Both groups of animals underwent a 40-min dynamic contrast-enhanced MRI using radio frequency spoiled gradient echo imaging sequence after injection of Gd-labeled MS325. Contrast uptake and clearance curves for cortex and medulla were determined from acquired MR images. Compared with controls, proteinuric rats exhibited significantly lower elimination rate constants. The use of gadopentetate dimeglumine (Gd-DTPA) as a contrast agent showed smaller and less specific differences between proteinuric and control groups. In rats with one proteinuric kidney (PAN-treated) and one normal kidney (transplanted from a normal rat), MRI using MS325 was able to differentiate between the two kidneys. The results suggest that MRI with an albumin-bound blood pool contrast agent may be a useful noninvasive way to localize proteinuria. If this technique can be successfully applied in human patients, it may allow for the localization of proteinuria after kidney transplant and thereby provide a noninvasive way to detect disease affecting the renal allograft.

Animals↗
PubMed2005

Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. STUDY DESIGN: We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. RESULTS: Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. CONCLUSIONS: These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

Adolescent↗
PubMed2005

Idiopathic intracranial hypertension following kidney transplantation: a case report and review of the literature.

A pediatric kidney transplant recipient receiving tacrolimus for immunosuppression experienced symptoms consistent with idiopathic intracranial hypertension. The diagnosis of idiopathic intracranial hypertension and possible secondary causes of intracranial hypertension are reviewed in association with the patient's clinical course. Treatment options for the reversal of intracranial hypertension are summarized. Because of the complexity of associated conditions in kidney transplant recipients, symptoms of persistent headaches, visual changes and nausea and vomiting should be promptly investigated by fundoscopic examination in the setting of immunosuppression therapy to prevent vision loss.

Child↗
PubMed2005

Strategies for minimizing immunosuppression in kidney transplantation.

Immunosuppression remains the cause of most morbidity following organ transplantation. However, its use is also responsible for the outstanding graft and patient survival rates commonplace in modern transplantation. Thus, the predominant challenge for transplant clinicians is to provide a level of immunosuppression that prevents graft rejection while preserving immunocompetence against environmental pathogens. This review will outline several strategies for minimizing or tailoring the use of immunosuppressive drugs. The arguments for various strategies will be based on clinical trial data rather than animal studies. A distinction will be made between conventional immunosuppressive drug reduction based on over-immunosuppression, and newer induction methods specifically designed to lessen the need for chronic immunosuppression. Based on the available data we suggest that most patients can be transplanted with less immunosuppression than is currently standard.

Dose-Response Relationship, Drug↗
PubMed2005

Functionally significant renal allograft rejection is defined by transcriptional criteria.

Renal allograft acute cellular rejection (ACR) is a T-cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T-cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub-clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT-PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up-regulated during effector T(H)1 T-cell activation, most significantly the transcription factor T-bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Adult↗
PubMed2005

Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion.

T-cell depletion facilitates reduced immunosuppression following organ transplantation and has been suggested to be pro-tolerant. However, the characteristics of post-depletional T cells have not been evaluated as they relate to tolerance induction. We therefore studied patients undergoing profound T-cell depletion with alemtuzumab or rabbit anti-thymocyte globulin following renal transplantation, evaluating the phenotype and functional characteristics of their residual cells. Naive T cells and T cells with potential regulatory function (CD4+CD25+) were not prevalent following aggressive depletion. Rather, post-depletion T cells were of a single phenotype (CD3+CD4+CD45RA-CD62L-CCR7-) consistent with depletion-resistant effector memory T cells that expanded in the first month and were uniquely prevalent at the time of rejection. These cells were resistant to steroids, deoxyspergualin or sirolimus in vitro, but were calcineurin-inhibitor sensitive. These data demonstrate that therapeutic depletion begets a limited population of functional memory-like T cells that are easily suppressed with certain immunosuppressants, but cannot be considered uniquely pro-tolerant.

Alemtuzumab↗
PubMed2004

The clinical application of monoclonal antibody therapies in renal transplantation.

Monoclonal antibodies have become valuable tools for the precise clinical manipulation of the immune system. These highly specific proteins have proven their usefulness in both the treatment and prevention of organ transplant rejection. Indeed, they are the centrepieces of many evolving regimens designed to reduce or eliminate the need for chronic immunosuppression. This manuscript will review the monoclonal antibodies that have made their way into the clinic either as experimental therapies or approved drugs. It will provide a general overview of this class of agents and their mechanisms of action. Standard therapies and potential new applications will be described.

Animals↗
PubMed2003

Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).

BACKGROUND: Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion. METHODS: Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis. RESULTS: Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels. CONCLUSIONS: T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.

Adult↗
PubMed2003

Inhibition of prolyl-4-hydroxylase ameliorates chronic rejection of mouse kidney allografts.

Interstitial fibrosis, glomerulosclerosis and arteriosclerosis are the major components of chronic allograft nephropathy (CAN), the leading cause of late graft failure after transplantation. To investigate the mechanism of collagen deposition in CAN, we studied the effects of prolyl-hydroxylase inhibitor (PHI), an enzyme essential for collagen formation, using a mouse model of kidney transplantation. Kidneys from H-2b mice were transplanted into MHC-incompatible H-2d recipients (allografts) and at 3 weeks post-transplant, received either PHI or vehicle treatment daily for 3 weeks. At 6 weeks post-transplant, GFR was significantly improved in the allografts receiving PHI (3.3 +/- 0.5 mL/min/kg) compared with those receiving vehicle (1.8 +/- 0.5 mL/min/kg, p < 0.05), while renal function was relatively unimpaired in the nonrejecting isografts (6.45 +/- 0.53 mL/min/kg). Allografts had histologic changes of CAN but the severity was significantly reduced with PHI treatment compared with vehicle, with reductions in interstitial inflammation and fibrosis. Furthermore, TGFâ and connective tissue growth factor mRNA expression was enhanced in both allograft groups compared with the isografts. In conclusion, PHI-treated allografts had improved renal function and reduced the severity of renal injury as a result of CAN. Inhibition of matrix synthesis may be a useful adjunct in ameliorating the development of CAN in humans.

Animals↗
PubMed2002

BK virus and SV40 co-infection in polyomavirus nephropathy.

BACKGROUND: Polyomavirus (PV) nephropathy has been attributed to reactivation of BK virus (BKV) or more rarely JC virus (JCV). The simian virus (SV) 40 is PV that was likely introduced into the human population through contaminated vaccines. The purpose of this study was to identify and characterize the PV that is associated with PV nephropathy. METHODS: The clinical diagnosis of PV nephropathy (PVN) was made in patients with acute deterioration in renal function whose renal biopsies showed typical viral cytopathic changes in tubular epithelial cells and staining for PV T antigen. Polymerase chain reaction (PCR) amplification of DNA from peripheral blood mononuclear cells (PBMC), urinary cells, and renal biopsy tissue was performed using specific primers for the transcription control regions of BKV, JCV, and SV40, respectively. RESULTS: Six cases of PV nephropathy were identified in 91 renal transplant recipients (7%). Immunosuppressive therapy was modified in all patients. Renal function stabilized or improved in four patients and deteriorated in two patients, and one patient has lost his allograft, after follow-up from 2 to 25 months. PCR detection demonstrated BKV genome in three of five PBMC samples, six of six urinary cell samples, and two of four renal biopsies. SV40 genome was detected in two of five PBMC samples, one of six urinary cell samples, and two of four renal biopsies. Infectious SV40 and BKV was demonstrated in CV-1 co-cultures using urine from one patient. JCV was not detected in any PVN sample. Co-infection with BKV and SV40 was found in two PVN patients. Urine samples obtained 12 months after transplant from 26 transplant recipients without PVN on simultaneous protocol renal biopsy were analyzed by PCR; BKV genome was demonstrated in 5 of 25 samples, JCV genome was demonstrated in 3 of 25 samples, and SV40 genome was demonstrated in 0 of 25 samples. CONCLUSION: The authors report molecular evidence that co-infection with BKV and SV40 occurs in renal transplant patients with PVN, suggesting that SV40 may contribute to PVN after renal transplant.

Adult↗
PubMed2002

Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy.

Renal allograft recipients generally need to take several immunosuppressive agents for life. Calcineurin inhibitors and glucocorticosteroids are the mainstays of most regimens but have undesirable chronic effects. We postulated that aggressive T-cell depletion combined with the newer immunosuppressant sirolimus would permit transplantation without multidrug treatment. We therefore tested T-cell depletion with rabbit antithymocyte globulin followed by sirolimus monotherapy in 12 patients in an open-label study. This approach was tolerated well, and all patients achieved excellent renal function, and most did not need chronic steroid treatment or calcineurin inhibitors. Rejection was typically correlated with low concentrations of sirolimus, indicating continued dependence on maintenance immunosuppression.

Adult↗