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Biomedical subjects

A S MacDonald

Publications and source records attributed to A S MacDonald.

At least 19 recordsLinked to original sources
PubMed2003

Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation.

A 10-year experience with the immunosuppressive drug rapamycin that begins in the laboratory then extends through multicentre trials in combination with cyclosporine in kidney transplant recipients, exploration of its use as a single agent and in combination with tacrolimus, and its potential in nonrenal organs is described. Rapamycin is a potent inhibitor of endothelial injury in rat aortic allografts. When added to full-dose cyclosporine it achieves low rejection rates, but it augments the nephrotoxicity and hyperlipidemia of cyclosporine. On the other hand, it allows discontinuation of calcineurin inhibitors in stable kidney and liver patients suffering from nephrotoxicity late posttransplant. At least in Caucasian patients, discontinuation of cyclosporine is possible as early as 3 months post-kidney transplant. In combination with low-dose tacrolimus, exceptionally low rates of rejection were seen in recipients of kidney, pancreas, and liver recipients with preservation of excellent renal function. These pilot studies have been confirmed in several single-centre and, more recently, multicentre trials in kidney and pancreas transplantation. The side-effect profile of hyperlipidemia, lymphocoeles, delayed wound healing, and possible liver effects are coming into focus, and ways of minimizing these problems being introduced. The lessons learned include the need for early adequate blood levels, the lack of correlation between dose and drug exposure, and the potency that allows marked dose reductions in calcineurin inhibitors and steroids.

Animals↗
PubMed2001

A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection.

Infections with the helminth parasite Brugia malayi share many key features with Th2-mediated allergic diseases, including recruitment of eosinophils. We have investigated the dynamics of inflammatory cell recruitment under type 2 cytokine conditions in mice infected with B. malayi. Among the cells recruited to the site of infection is a novel population of "alternatively activated" macrophages that ablate cell proliferation and enhance Th2 differentiation. By profiling gene expression in this macrophage population, we found a dramatic up-regulation of a recently described eosinophil chemotactic factor, eosinophil chemotactic factor-L/Ym1, representing over 9% of clones randomly selected from a cDNA library. Because B. malayi is known to secrete homologs (Bm macrophage migration inhibitory factor (MIF)-1 and -2) of the human cytokine MIF, we chose to investigate the role this cytokine mimic may play in the development of the novel macrophage phenotype observed during infection. Strikingly, administration of soluble recombinant Bm-MIF-1 was able to reproduce the effects of live parasites, leading both to the up-regulation of Ym1 by macrophages and a marked recruitment of eosinophils in vivo. Because activity of Bm-MIF-1 is dependent upon an amino-terminal proline, this residue was mutated to glycine; the resultant recombinant (Bm-MIF-1G) was unable to induce Ym1 transcription in macrophages or to mediate the recruitment of eosinophils. These data suggest that macrophages may provide a crucial link between helminth parasites, their active cytokine mimics, and the recruitment of eosinophils in infection.

Animals↗
PubMed2001

CD8- dendritic cell activation status plays an integral role in influencing Th2 response development.

Whether dendritic cells (DC) play a passive or active role in Th2 response induction is poorly understood. In this study, we show that CD8- DC pulsed with Th2-polarizing Ag (soluble egg Ag (SEA)) from Schistosoma mansoni potently stimulate Th2 responses in vivo and in vitro while failing to undergo a conventional maturation process. Thus, in contrast to DC pulsed with the Th1 response inducing Ag Propionebacterium acnes, SEA-exposed DC exhibit a phenotype that is most similar to that of immature DC, failing to up-regulate expression of CD40, CD54, CD80, CD86, or OX40L; producing no detectable IL-4, IL-10, or IL-12; and displaying only a minor increase in MHC class II expression. Importantly, in vitro derived DC exposed to SEA were phenotypically similar to CD8- DC isolated from active S. mansoni infection. By discriminating between different types of pathogen and responding appropriately, CD8- DC play a major role in the decision process to mount either a Th1 or Th2 response.

Animals↗
PubMed2001

A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts.

BACKGROUND: Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. METHODS: Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. RESULTS: Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. CONCLUSIONS: The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.

Acute Disease↗
PubMed2001

Orthotopic liver transplantation using low-dose tacrolimus and sirolimus.

Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.

Adolescent↗
PubMed2001

The role of psychological functioning in morbid obesity and its treatment with gastroplasty.

BACKGROUND: The authors evaluated the psychological characteristics of the morbidly obese. The condition-specific and quality-of-life characteristics of a large sample of vertical banded gastroplasty (VBG) patients were evaluated. The role that these psychological characteristics play in moderating the success of gastroplasty surgery, as well as the impact of surgery on quality of life, was examined. METHODS: This is a cross-sectional evaluative study of a clinical samples, with longitudinal follow-up and with non-surgical comparison groups. 89 morbidly obese individuals were assessed before VBG (but after having been accepted for surgery) and again 1.27 years after surgery. This group represents 98% of the patients who received VBG (i.e., a 2% dropout rate). We used established psychological measures (quality of life, adjustment to obesity, functional impairment, and eating attitudes), including a scale developed by our group specifically for morbid obesity, to identify distinct psychological profiles of the morbidly obese before surgery. RESULTS: The three profile groups differed significantly in psychological characteristics, ranging from high functioning (little emotional distress, functional impairment or dysfunctional eating) to poor functioning (high emotional distress, functional impairment and dysfunctional eating). The subgroups did not differ on pre-surgical weight, and did not differ from morbidly obese groups not seeking surgery. For the surgery group, regardless of pre-surgery psychological profile, VBG produced significant weight loss, maintained at 1 year after surgery. As well, surgery resulted in significant improvements in quality of life and psychological adjustment, especially in the profile group initially presenting with psychological disturbance. CONCLUSION: There was no evidence to suggest that those with pre-surgical psychological difficulties did more poorly with VBG. These data call into question screening out individuals with psychological problems from gastroplasty surgery. Furthermore, psychological difficulties, if they exist, appear more related to the nature of morbid obesity than to the character of the individual. Psychological difficulties pre-surgery were normalized following surgery.

Adolescent↗
PubMed2000

AMPA receptor subunit expression in trigeminal neurons during postnatal development.

Trigeminal motoneurons (Mo5) and mesencephalic trigeminal neurons (Me5) are important constituents of the neural circuitry responsible for jaw movements. Non-N-methyl-D-aspartate (NMDA) glutamate receptors are a critical component of the brainstem circuitry responsible for reflex and centrally activated jaw movements; however, little is known about the expression of these receptors in neonatal oral-motor circuitry. Receptor immunohistochemistry using affinity-purified polyclonal antibodies directed against GluR1, GluR2/3/4c, and GluR4, respectively, and a monoclonal antibody directed against the GluR2 subunit, were used in rats at postnatal day (P)1, P3, P5, P10, P19-21, P32-35, and P60 to describe the expression of the alpha-amino-d-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in Mo5 and Me5 neurons. In Mo5, immunoreactivity was noted for all antibodies throughout the time frame sampled. Neurons in caudal portions of Me5 displayed immunoreactivity to each antibody except at P60 when GluR2 immunoreactivity was absent. Neurons located in rostral Me5 displayed GluR2/3/4c and GluR4 immunoreactivity throughout the time frame, GluR1 immunoreactivity emerged at P3 and a transient expression of GluR2 expression was observed between P10 and P32-35. The lack of labeling of some neurons in both regions, coupled with differences in temporal expression, suggests that there are differences in the AMPA receptor phenotype within and between Mo5 and Me5 during postnatal development. Differences in AMPA subunit composition suggest a complex role for AMPA-mediated glutamatergic neurotransmission in brainstem circuits controlling jaw movements.

Age Factors↗
PubMed2000

Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial experience.

BACKGROUND: The aim of this study is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. METHODS: Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. RESULTS: In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233+/-34 to 210+/-56 micromol/liter (P<0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. CONCLUSIONS: RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Adult↗
PubMed2000

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

BACKGROUND: Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. METHODS: Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. RESULTS: Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon's opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%); P=0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. CONCLUSIONS: Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

Adult↗
PubMed2000

Role of IL-6 in directing the initial immune response to schistosome eggs.

The eggs of Schistosoma mansoni are strong inducers of a Th2 response, and previous work has shown that Ag-specific IL-6 is produced within 24 h after the injection of eggs into mice. Investigations to determine the role of IL-6 in orchestrating the early response to schistosome eggs have revealed that IL-12 is rapidly produced in lymph node cell cultures from egg-injected mice. This "early" IL-12 primes for the production of IL-6 and IFN-gamma, for in IL-12-/- mice egg injection fails to stimulate increased production of either of these cytokines. Furthermore, IL-6 also up-regulates IL-10 production which, together with IL-6, negatively regulates IL-12 and IFN-gamma production. Finally, IL-10 down-regulates the production of its inducer, IL-6. These data indicate that the anti-inflammatory role of IL-6 may be effected through negative regulation of type 1 (IFN-gamma) and type 1-associated (IL-12) cytokines either directly (by IL-6) or indirectly (through the induction of IL-10) and suggest that one mechanism by which eggs may support the development of Th2 responses is through the negative regulation of the type 1 response.

Animals↗
PubMed2000

Sirolimus-tacrolimus combination immunosuppression.

A series of 32 recipients of liver, kidney, or pancreas transplants who were treated with sirolimus and low-dose tacrolimus experienced a low rate of rejection and excellent graft function without drug-related toxic effects.

Adolescent↗
PubMed2000

Antigen-presenting cells recruited by Brugia malayi induce Th2 differentiation of naïve CD4(+) T cells.

A key feature of nematode infection is a bias towards a type 2 immune response. To investigate the role that antigen-presenting cells (APC) may play in promoting this bias, we used adherent peritoneal exudate cells (PEC) recruited in response to the filarial nematode Brugia malayi, to stimulate naïve T cells from pigeon cytochrome c (PCC)-specific TCR transgenic (PCC-tg) mice. Although the proliferation of PCC-tg T cells was inhibited by parasite- induced PEC during primary stimulation, they proliferated normally upon secondary stimulation and were not rendered anergic. However, PCC-tg T cells primed by suppressive APC differentiated into IL-4-producing Th2 cells upon secondary stimulation instead of IFN-gamma-producing Th1 cells, as has been previously described. Studies with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled cells indicated that Th2 differentiation was associated with the inhibition of (or failure to stimulate) IFN-gamma production during primary stimulation. Interestingly, blocking antibodies against TGF-beta (but not IL-10) restored the differentiation of IFN-gamma-producing Th1 cells. Identical results with CFSE-labeled cells were obtained using purified IL-4-dependent F4/80(+) macrophages. These data indicate that T cells exposed to parasite-induced alternatively activated macrophages are driven towards Th2 differentiation. This may be an important factor in the Th2 bias that accompanies nematode infection.

Animals↗
PubMed2000

Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact.

The cytokine microenvironment is thought to play an important role in the generation of immunoregulatory cells. Nematode infections are commonly associated with Th2 cytokines and hyporesponsive T cells. Here we show that IL-4-dependent macrophages recruited in vivo by the nematode parasite Brugia malayi actively suppress the proliferation of lymphocytes on co-culture in vitro. These alternatively activated macrophages block proliferation by cell-to-cell contact, implicating a receptor-mediated mechanism. Further, the proliferative block is reversible and is not a result of apoptosis. Suppressed cells accumulate in the G1 and G2/M phase of the cell cycle. Interestingly, the G1 and G2/M block correlates with increased levels of Ki-67 protein, suggesting a mechanism that affects degradation of cell cycle proteins. We also show that, in addition to lymphocyte cell lines of murine origin, these suppressive cells can inhibit proliferation of a wide range of transformed human carcinoma lines. Our data reveal a novel mechanism of proliferative suppression induced by a parasitic nematode that acts via IL-4-dependent macrophages. These macrophages may function as important immune regulatory cells in both infectious and noninfectious disease contexts.

Animals↗