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Biomedical subjects

R Y Calne

Publications and source records attributed to R Y Calne.

At least 19 recordsLinked to original sources
PubMed2005

Prope tolerance--the future of organ transplantation from the laboratory to the clinic.

This is a short review of tolerance from the point of view of the clinician. Various examples of tolerance occurring in patients and animal models that relate to the clinical experience are described. It is suggested that there may be different mechanisms by which tolerance is achieved, but, from the patient's point of view operational, tolerance is the goal whereby, after a short induction procedure, the patient will maintain good function in the grafted organ indefinitely without maintenance immunosuppression. It is pointed out that such a goal may be difficult to achieve with any given protocol due to the enormous variation between donors and recipients of organ grafts of tissue matching, innate immune reactivity, and susceptibility to disturbance of a tolerant state by infections or allergic reactions. Thus, the case is made for prope or almost tolerance in which graft acceptance is maintained by a low, nontoxic dosage of maintenance immunosuppression which may not be required indefinitely.

Animals↗
PubMed2004

Prope tolerance: the future of organ transplantation--from the laboratory to the clinic.

This is a short review of tolerance from the point of view of the clinician. Various examples of tolerance occurring in patients and animal models that relate to the clinical experience are described. There may be different mechanisms by which tolerance is achieved, but from the patient's point of view operational tolerance is the goal whereby, after a short induction procedure, the patient will maintain good function in the grafted organ indefinitely without maintenance immunosuppression. Such a goal may be difficult to achieve with any given protocol because of the enormous variation between donors and recipients of organ grafts in tissue matching, innate immune reactivity, and susceptibility to disturbance of a tolerant state by infections or allergic reactions. Thus the case is made for prope or "almost" tolerance in which graft acceptance is maintained by a low, nontoxic dosage of maintenance immunosuppression that may not be required indefinitely.

Animals↗
PubMed2003

Adult small intestinal transplantation in England and Wales.

BACKGROUND: In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented. METHODS: Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery. RESULTS: Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent. CONCLUSION: Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Adult↗
PubMed2003

Relapsing encephalopathy following small bowel transplantation.

We report a case of a 40-year-old man presenting with relapsing encephalopathy 4 years post-intestinal transplantation. Each episode was preceded by symptoms suggestive of subacute intestinal obstruction, marked dehydration, and, on one occasion, grade 4 encephalopathy. Physical examination revealed hypertonia, clonus, and hyperreflexia. Biochemistry was consistent with renal impairment, metabolic alkalosis, hyperammonaemia, and normal liver function. Plain radiographs and abdominal computed tomography revealed dilated proximal small bowel loops, and barium radiography demonstrated a strictured distal anastomosis. Hydrogen breath testing indicated bacterial overgrowth. Following rehydration and antibiotic therapy, the patient recovered fully between episodes. Further episodes of encephalopathy did not recur following resection of the distal anastomotic stricture and resolution of bacterial overgrowth. Unfortunately, one year later the patient died of pneumonia. To the best of our knowledge, encephalopathy secondary to intestinal transplant related porto-caval shunt and bacterial overgrowth in strictured bowel has not been previously reported but might have implications for the management of future patients.

Adult↗
PubMed2001

Combined transplantation of the heart, lung, and liver.

Combined transplantation of the heart, lung, and liver may be indicated in patients with either end-stage respiratory failure complicated by advanced liver disease or end-stage liver failure complicated by advanced lung disease. A retrospective review of nine patients who underwent combined heart-lung-liver transplantation in Cambridge (1986-99) was carried out. The 1-year and 5-year actuarial survival was 56% and 42%, respectively. Combined heart-lung-liver transplantation is a feasible option for a few patients and has a 5-year survival similar to heart-lung transplantation but with a lower incidence of acute and chronic rejection.

Adolescent↗
PubMed2001

The future of organ transplantation: from the laboratory to the clinic.

This is a short review of tolerance from the point of view of the clinician. Various examples of tolerance occurring in patients and animal models that relate to the clinical experience are described. It is suggested that there may be different mechanisms by which tolerance is achieved, but from the patient's point of view operational tolerance is the goal, whereby, after a short induction procedure, the patient will maintain good function in the grafted organ indefinitely without maintenance immunosuppression. It is pointed out that such a goal may be difficult to achieve with any given protocol due to the enormous variation between donors and recipients of organ grafts of tissue matching, innate immune reactivity and susceptibility to disturbance of a tolerant state by infections or allergic reactions. Thus the case is made for prope or almost tolerance in which graft acceptance is maintained by a low, non-toxic dosage of maintenance immunosuppression that may not be required indefinitely.

Alemtuzumab↗
PubMed2000

Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days.

BACKGROUND: It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates. METHODS: Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs. FINDINGS: The three control animals transplanted with livers from unmodified pigs survived for less than 12 hr. Baboons transplanted with livers from h-DAF transgenic pigs survived for 4 and 8 days. Hyperacute rejection was not detected in the baboons transplanted with hDAF transgenic pig livers; however, it was demonstrated in the three transplants from unmodified pigs. Baboons transplanted with livers from h-DAF transgenic pigs were extubated at postoperative day 1 and were awake and able to eat and drink. In the recipients of hDAF transgenic pig livers the clotting parameters reached nearly normal levels at day 2 after transplantation and remained normal up to the end of the experiments. In these hDAF liver recipients, porcine fibrinogen was first detected in the baboon plasma 2 hr postreperfusion, and was present up to the end of the experiments. One animal was euthanized at day 8 after development of sepsis and coagulopathy, the other animal arrested at day 4, after an episode of vomiting and aspiration. The postmortem examination of the hDAF transgenic liver xenografts did not demonstrate rejection. INTERPRETATION: The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.

Acute Disease↗
PubMed2000

Prope tolerance: a step in the search for tolerance in the clinic.

Following the demonstration by Knechtle and colleagues that profound T cell depletion in rhesus monkeys treated with a CD3 diphtheria immunotoxin resulted in tolerance to renal allografting, we have used a similarly depleting protocol that, in addition, depletes B cells in recipients of a cadaveric renal transplant. The humanized antiCD52 monoclonal antibody had a rapid depleting effect when given intravenously, 20 mg on days 0 and 1 after-renal transplantation, to 31 patients. At 48 hours after the second dose of low dose monotherapy cyclosporine (Neoral) was given to maintain blood levels averaging 100 ng/ml. Initially no other immunosuppression was given. With an average follow-up of 24 months all but one of the patients are alive, 29 with intact functioning grafts. There have been five rejection episodes, which responded to pulsed steroid treatment. One patient had a recurrence of her original disease. Two patients developed opportunistic infections, which responded to therapy; and one patient with severe heart failure at the time of surgery died from this condition after 11 months. Currently 29 patients are still on the original low dose cyclosporine monotherapy. The outcome in this cohort of patients has been encouraging, with efficacy that compares favorably to our conventional triple therapy but in most cases allows the patients to be steroid-free on low dose immunosuppressive monotherapy. The maintenance treatment is inexpensive and should be beneficial in the context of tight budgetary constraints worldwide. The patients who avoided steroids are pleased with this aspect of the protocol. A randomized trial comparing this treatment with standard therapy is planned.

Animals↗
PubMed2000

Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles.

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.

Animals↗
PubMed2000

Immunological tolerance--the liver effect.

The developing immune system in the embryo is programmed to accept all its own tissues as self-products and not react against them. It has been the aim of transplantation research for the past 40 years to try and manipulate the developed immune system temporarily to a similar status to that in the embryo at the time of an organ graft, so that the organ graft is accepted but immunity generally is not interfered with. Such a state is known as immunological tolerance and can be produced in the laboratory by a number of special techniques, none of which is appropriate for clinical use in organ grafting. In pigs and rats, an allografted liver can sometimes survive permanently without any immunosuppressive treatment in immunologically mature animals.

Animals↗
PubMed1999

Potential for improved therapeutic index of FK506 in liposomal formulation demonstrated in a mouse cardiac allograft model.

BACKGROUND: FK506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue immunosuppressive agent. Despite these benefits, the potential value of FK506 is limited by toxic side effects that result in a narrow therapeutic index. By encapsulating the active drug within liposomes (LipoFK506), a new formulation has been developed that might improve this therapeutic index. METHODS: The biodistribution of tritiated-FK506 administered i.v. showed that the drug remained associated with the liposomal carrier in vivo, and that its tissue distribution was increased in heart and spleen compared to nonliposomal FK506. The immunosuppressive efficacy of lipoFK506 compared with conventional FK506 formulation was tested in vivo. CBA (H2k) mice were engrafted with BALB/c (H2d) mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg LipoFK506, from day 0 to 14. RESULTS: At day 7 the blood trough level of FK506 in the FK506 group was 10-fold higher (25 microg/L) than that in the LipoFK506 group. In both groups the median heart allograft survival was similar at around 26 days. The possibility that FK506, or LipoFK506, might influence antibody-mediated tolerogenesis was addressed in the same model: neither formulation prevented tolerance induction by CD4 and CD8 blockade. CONCLUSION: LipoFK506 is a novel formulation of FK506 that is efficacious at low blood trough FK506 levels. This property has a direct potential benefit for clinical organ transplantation.

Animals↗