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Biomedical subjects

Mark A Hardy

Publications and source records attributed to Mark A Hardy.

At least 19 recordsLinked to original sources
PubMed2005

Acute and hyperacute humoral rejection in kidney allograft recipients treated with anti-human thymocyte antibodies.

Equine and rabbit antihuman thymocyte globulins (ATGs) have been used in renal transplantation for prevention and treatment of acute rejection. We now report that hyperacute and acute antibody-mediated rejection of renal allografts occurred in three newly transplanted patients who received ATG for induction therapy. Antibody studies performed using complement-dependent cytotoxicity, flow cytometry, enzyme-linked immunosorbent assay, and Luminex yielded negative results for antilymphocytic and antiendothelial cell antibodies in the pretransplant sera obtained from these patients. ATG treatment was initiated at the time of transplantation. One of the patients experienced hyperacute rejection and required transplant nephrectomy within 24 h of transplantation. The other two patients developed acute antibody-mediated rejection within 14 days after transplantation. None of the patients developed antihuman leukocyte antigen antibodies when humoral rejection occurred. However, xenoantibodies that strongly bound to human lymphocytes and, importantly, to activated endothelial cells, were identified in the sera obtained at the time of humoral rejection. Hence, our results strongly implicate ATG in the induction of antibody-mediated rejection of kidney allografts. Flow cytometry testing of ATG reactivity to endothelial cells may be useful in identifying and discarding the ATG lots containing xenoantibodies that can bind to activated endothelial cells of the transplant.

Adolescent↗
PubMed2005

A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation.

Normal saline (NS; 0.9% NaCl) is administered during kidney transplantation to avoid the risk of hyperkalemia associated with potassium-containing fluids. Recent evidence suggests that NS may be associated with adverse effects that are not seen with balanced-salt fluids, e.g., lactated Ringer's solution (LR). We hypothesized that NS is detrimental to renal function in kidney transplant recipients. Adults undergoing kidney transplantation were enrolled in a prospective, randomized, double-blind clinical trial of NS versus LR for intraoperative IV fluid therapy. The primary outcome measure was creatinine concentration on postoperative Day 3. The study was terminated for safety reasons after interim analysis of data from 51 patients. Forty-eight patients underwent living donor kidney transplants, and three patients underwent cadaveric donor transplants. Twenty-six patients received NS, and 25 patients received LR. There was no difference between groups in the primary outcome measure. Five (19%) patients in the NS group versus zero (0%) patients in the LR group had potassium concentrations >6 mEq/L and were treated for hyperkalemia (P = 0.05). Eight (31%) patients in the NS group versus zero (0%) patients in the LR group were treated for metabolic acidosis (P = 0.004). NS did not adversely affect renal function. LR was associated with less hyperkalemia and acidosis compared with NS. LR may be a safe choice for IV fluid therapy in patients undergoing kidney transplantation.

Acidosis↗
PubMed2004

Consensus opinion from the antibody working group on the diagnosis, reporting, and risk assessment for antibody-mediated rejection and desensitization protocols.

During the past few decades, much of the experimental and clinical effort in solid-organ transplantation has been directed toward ameliorating or abrogating T-cell-mediated responses. As a result, universally understood and accepted nomenclature and diagnostic criteria have evolved. Humoral immunity in transplantation has yet to undergo a similar renaissance. Readers of transplant journals regularly find it difficult and often impossible to interpret data on the diagnosis and management of antibody-mediated rejection. The Antibody Working Group was assembled in an attempt to provide guidelines for the standardization of nomenclature, diagnostic criteria, reporting, antibody profiling, and risk assessment.

Graft Rejection↗
PubMed2004

Identification of tissue-restricted transcripts in human islets.

The purpose of our study was to identify transcripts specific for tissue-restricted, membrane-associated proteins in human islets that, in turn, might serve as markers of healthy or diseased islet cell masses. Using oligonucleotide chips, we obtained gene expression profiles of human islets for comparison with the profiles of exocrine pancreas, liver, and kidney tissue. As periislet presence of type 1 interferon is associated with the development of type 1 diabetes, the expression profile of human islets treated ex vivo with interferon-alpha2beta (IFNalpha2beta) was also determined. A set of genes encoding transmembrane- or membrane-associated proteins with novel islet-restricted expression was resolved by determining the intersection of the islet set with the complement of datasets obtained from other tissues. Under the influence of IFNalpha2beta, the expression levels of transcripts for several of the identified gene products were up- or down-regulated. One of the islet-restricted gene products identified in this study, vesicular monoamine transporter type 2, was shown to bind [3H]dihydrotetrabenazine, a ligand with derivatives suitable for positron emission tomography imaging. We report here the first comparison of gene expression profiles of human islets with other tissues and the identification of a target molecule with possible use in determining islet cell masses.

Culture Techniques↗
PubMed2004

The organ center of the United Network for Organ Sharing and twenty years of organ sharing in the United States.

The increasing size of the transplant waiting list and the increasing use of expanded criteria donors places a premium on efficient use of recovered organs. Maximal organ utilization often necessitates organ sharing between transplant organizations. Optimal organ sharing requires rapid, integrated communication of donor information combined with expedited organ transportation. For more than 20 years, the United Network for Organ Sharing's Organ Center has fulfilled this task for the United States transplant community. This overview details a brief history of United States organ sharing and the role played by the Organ Center. The current scope and modes of Organ Center operations are detailed.

Humans↗
PubMed2004

Rat CD8+ FOXP3+ T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection.

Human CD8+ FOXP3+ T suppressor cells (TS) were previously shown to induce the expression of the inhibitory receptors, Immunoglobulin-like transcript (ILT) 3 and ILT4 on dendritic and endothelial cells, rendering them tolerogenic to allogeneic T cells. We have demonstrated the importance of CD8+ TS in a rat model of heart allo-transplantation. Tolerance was induced in ACI recipients by multiple transfusions of UVB-irradiated blood from Lewis heart donors. CD8+ T cells from tolerant ACI rats expressed FOXP3, transferred tolerance to naive secondary hosts and induced the upregulation of the inhibitory receptor, paired immunoglobulin-like receptor (PIR)-B, an ILT4 orthologue, in Lewis dendritic cells (DC) and heart endothelial cells (EC). When long-term surviving Lewis heart allografts with PIR-B+ EC were retransplanted from a primary to a secondary ACI recipient they did not elicit rejection. This study focuses attention on the need to develop agents that act directly on graft EC in order to achieve tolerance.

Animals↗
PubMed2003

Role of CD41CD251 regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.

BACKGROUND: Immunization with allo-major histocompatibility complex peptide induces operational tolerance, whereas thymectomy abrogates this effect. We hypothesized that recent thymic emigrants with regulatory function are important in the induction of acquired transplant tolerance in this system. METHODS: In this study, we examined the possibility of restoring transplant tolerance to thymectomized (TMX) ACI recipients with concomitant adoptive transfer of syngeneic T cells indirectly primed with a single immunodominant Wistar Furth allo-major histocompatibility complex class I peptide (peptide 5, residues 93-109) and unmodified thymocytes or CD4+CD25+ thymic T cells. RESULTS: Co-transfer of in vivo allopeptide-primed T cells and naive syngeneic thymic T cells on day -7 restored permanent acceptance of cardiac allografts to 70% of transiently antilymphocyte serum-immunosuppressed TMX recipients. Similarly, the adoptive transfer of allopeptide-primed T cells led to 100% donor-specific permanent graft acceptance among transiently antilymphocyte serum-immunosuppressed TMX recipients with renal subcapsular syngeneic thymic grafts. To demonstrate the role of regulatory T cells among new thymic emigrants in the induction of tolerance, we showed that the co-transfer of CD4+CD25+ but not CD4+CD25- thymic T cells with allopeptide-primed syngeneic T cells restored tolerance to TMX recipients. It seems that the induction of transplant tolerance in this system is dependent on the presence of CD4+CD25+ regulatory T cells among the recent thymic emigrants. CONCLUSIONS: This study suggests that CD4+CD25+ regulatory T cells specific for the induction of transplant tolerance are similar in origin, phenotype, and function to those involved in the maintenance of self-tolerance and the prevention of autoimmunity.

Adoptive Transfer↗
PubMed2003

Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory renal-transplant patients.

BACKGROUND: Antilymphocyte globulins have been used for the treatment and prevention of acute rejection in renal-allograft recipients. Thymoglobulin, rabbit antithymocyte globulin (RATG), has been shown to be effective for these indications and has been used primarily on an inpatient basis because of the recommendation that it be administered through a central line. METHODS: We retrospectively reviewed the charts of all patients treated with RATG since its first use in 1999. After premedication, the dose of RATG was administered over 4 to 6 hours, with 1,000 units of heparin and 20 mg of hydrocortisone to reduce the incidence of thrombosis and local tissue reaction. All adverse reactions were recorded. RESULTS: Eighteen patients underwent a total of 57 outpatient infusions. Of the 57 infusions, 52 (91%) were without complication. Five infusions (9%) were complicated by infiltrates. No serious reactions were noted. CONCLUSIONS: These data confirm that peripheral, outpatient administration of RATG is safe.

Acute Disease↗
PubMed2003

Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival.

BACKGROUND: Because the differential polarization of T cells in response to antigen presentation is dependent on the maturational state of dendritic cells (DCs), we hypothesized that the adoptive transfer of immature myeloid DCs (iMDCs) would prolong graft survival. METHODS: To evaluate this hypothesis, we studied the effects of transfer of iMDCs and mature myeloid DCs (mMDCs) on rat cardiac allograft survival. RESULTS: Whereas iMDCs that do not express costimulatory molecules induce allogeneic T-cell hyporesponsiveness in coculture studies, mMDCs that express high levels of major histocompatibility complex class II costimulatory and maturation molecules induce a robust allostimulatory T-cell response. Adoptive transfer of Wistar Furth iMDCs, unlike mMDCs, 7 days before cardiac transplantation significantly prolonged graft survival. It was important that adoptive transfer of iMDCs combined with 0.5 mL antilymphocyte serum (ALS) transient immunosuppression on day -7 led to donor-specific permanent graft survival in 50% of recipients. In contrast, adoptive transfer of mMDCs combined with ALS led to graft survival similar to that in recipients treated with ALS alone. Stimulation of CD4 T cells isolated from the spleen of unresponsive allograft recipients with donor antigen resulted in donor-specific hyporesponsiveness and production of interleukin (IL)-10 and transforming growth factor-beta but not IL-4 and interferon-gamma. The tolerant T-cell unresponsiveness was reversed by the addition of IL-2. CONCLUSION: Our data confirming the immunoregulatory effect of immature DCs indicate that induction of transplant tolerance by iMDCs is partly dependent on in vivo generation of regulatory T cells. This finding suggests that immunization with immature donor DCs has therapeutic potential for the induction of transplant tolerance and treatment of autoimmune diseases.

Adoptive Transfer↗
PubMed2003

Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease).

Nephrogenic fibrosing dermopathy or scleromyxedema-like illness of renal disease is a recently reported disorder. It manifests as scleromyxedema-like skin lesions without associated paraproteinemia, occurring in the setting of renal disease. In the majority of cases skin lesions of nephrogenic fibrosing dermopathy develop after hemodialysis or renal transplantation; however, the origin is still unknown. We report 4 new cases of nephrogenic fibrosing dermopathy and review the literature. The clinical and histopathologic features, differential diagnosis, possible etiology, and treatment options are reviewed.

Adult↗
PubMed2002

Peritransplant streptavidin recipient treatment prolongs rat cardiac allograft survival.

BACKGROUND: Because streptavidin shows high localization in inflamed tissues, it might also interfere with the proliferation of cells involved in allograft rejection. METHODS AND RESULTS: Treatment of naïve ACI recipients with 20 mg/kg streptavidin i.p. alone significantly prolonged Lewis cardiac allografts from a mean survival time of 9.8+/-0.7 days in controls to 19.8+/-6.5 days, with one recipient accepting the graft permanently (>250 days). Peritransplant streptavidin treatment combined with 0.5 ml of antilymphocyte serum (ALS) transient immunosuppression led to permanent graft survival (>250 days) in 6 of 10 recipients. Second-set skin grafts performed 60 days after the primary cardiac allograft were prolonged to 45 days, whereas the third party Wistar-Furth (WF) skin grafts were rejected in 15 days without the rejection of the primary Lewis cardiac allografts. Pathology of transplanted cardiac allografts at 100 days showed no mononuclear cell infiltration or chronic allograft vasculopathy. Streptavidin given for 5 days at 20 mg/kg caused a moderate initial weight loss but had no effect on hematologic, biochemical, and histologic parameters in the treated recipients. CONCLUSION: This study demonstrates that peritransplant recipient treatment with streptavidin combined with peritransplant ALS induces prolonged cardiac and second-set skin allograft survival. We conclude that recipient peritransplant streptavidin treatment may provide a new strategy for the induction of transplant tolerance.

Animals↗
PubMed2002

Results of crossmatch between chimpanzee lymphocytes and sera of highly sensitized potential renal transplant recipients.

BACKGROUND: We tested the hypothesis that patients with a high frequency of lymphocytotoxic antibodies against human cells are not highly sensitized to major histocompatibility complexes expressed by chimpanzee cells. METHODS: Sera from six "hopelessly" sensitized patients (percentage reactive antibodies (PRA) > 99%) on the renal transplant waiting list were crossmatched with peripheral blood lymphocytes from 10 chimpanzees. Lymphocytotoxic antibodies reacting with chimpanzee peripheral blood lymphocytes were identified. RESULTS: Three of the six patients with a high frequency of lymphocytotoxic antibodies against human cells had no xenospecific antibodies. CONCLUSION: Patients with a high frequency of lymphocytotoxic antibodies against human cells are not all panel-reactive to chimpanzees. Unilateral donor nephrectomy in non-human primates may offer an opportunity for safe expansion of the donor organ pool for these patients.

Animals↗
PubMedDate not supplied

A 360 degrees evaluation of a night-float system for general surgery: a response to mandated work-hours reduction.

PURPOSE: New York State Code 405 and societal/political pressure have led the RRC and ACGME to mandate strict limitations on resident work hours. In an attempt to meet these limitations, we have switched from the previous Q3 call schedule to a specialized night float (NF) system, the continuity-care system (CCS). The purpose of this CCS is to maximize resident duty time spent on direct patient care, operative experience, and outpatient clinics, while reducing duty hours spent on performing routine tasks and call coverage. The implementation of the CCS is the fundamental step in the restructuring of our residency program. In addition to a change in the call system, we added physician assistants to aid in performing some service tasks. We performed a 360 degrees evaluation of this work in progress. METHODS: In May 2002, the standard Q3 call system was abolished on the general surgery services at the New York Presbyterian Hospital, Columbia campus. Two dedicated teams were created to provide day and night coverage, a day continuity-care team (DCT) and a night continuity-care team (NCT). The DCTs, consisting of PGY1-5 residents, provide daily in-house coverage from 6 AM to 5 PM with no regular weekday night-call responsibilities. The DCT residents provide Friday night, Saturday, and daytime Sunday call coverage 3 to 4 days per month. The NCT, consisting of 5 PGY1-5 residents, provides nightly continuous care, 5 PM to 6 AM, Sunday through Thursday, with no other weekend call responsibilities. This system creates a schedule with less than 80 duty hours per week, on average, with one 24-hour period off a week, one complete weekend off per month, and no more than 24 hours of consecutive duty time. After 1 year of use, the system was evaluated by a 360 degrees method in which residents, residents' spouses, nurses, and faculty were surveyed using a Likert-type scale. Statistical significance was calculated using the Student t-test. Patient satisfaction was measured both by internal review of a patient complaint database as well as by the Press Ganey patient satisfaction surveys. RESULTS: Twenty-one residents, 10 residents' spouses, 11 general surgery faculty, and 16 nurses were surveyed. Statistically significant findings included reduced resident fatigue noted by all groups (residents, p = 0.01; resident spouses, p = 0.05; faculty, p < 0.0001; nurses, p < 0.0001). Further, residents reported more time for sleep at home (p = 0.0005) and more time for independent reading (p = 0.01). Residents' spouses reported increased availability for family events (p = 0.01). Nurses reported increased availability of residents (p = 0.0002), shorter times to physician identification of patient problems (p = 0.0086), improved resident-nursing communications (p = 0.0096), and increased ease of nursing duties (p < 0.0001). Faculty were the only responders who felt that continuity of patient care suffered with the new system (p = 0.02). The Press Ganey review showed improvement in the quality of care rendered as perceived by patients. CONCLUSIONS: The institution of a specialized NF or CCS for in-house coverage of general surgical services in a large metropolitan university hospital has had initial success in meeting the mandated changes in resident work hours. The CCS reduced resident fatigue, improved quality of resident life, and improved patient care as judged by patients and nurse.

Appointments and Schedules↗