BACKGROUND: We have previously shown that cytotoxic T lymphocytes (CTL) with alloreactivity were induced when Wistar Furth (WF; RT1u) rats were immunized with allogeneic Brown Norway (BN; RT1n) cells. In contrast, when BN rats were immunized with WF cells, the allospecific response was confined to alloreactive natural killer (NK) cells, and no CTL activity was observed. In this study, the effect of cyclosporine (CsA) on the activation of alloreactive NK cells in vivo was analyzed. METHODS: Distinct peritoneal effector cells from rats immunized with allogenic cells with or without concomitant CsA and/or interleukin (IL) 2 treatment were tested for specific cytolytic activity. Furthermore, the presumptive role of NK cells in rejection immunity was addressed in a cardiac graft model. RESULTS: The results showed that doses of CsA that completely inhibited the activation of alloreactive CTL, only marginally affected the activation of alloreactive NK cells. We also showed that CsA treatment failed to prolong graft survival in BN recipients of WF hearts. Treatment of BN rats with CsA/IL-2 during immunization with allogeneic WF cells resulted in concomitant induction of alloreactive NK cells and alloreactive CTL. CONCLUSIONS: We have demonstrated that CsA failed to suppress the activation of alloreactive NK cells. Consequently, the cardiac graft survival in the donor-recipient combination known to activate alloreactive NK cells was not significantly prolonged by CsA treatment, emphasizing the involvement of NK cells as effectors in organ rejection. Furthermore, the parallel emergence of alloreactive NK cells and CTL only in the presence of CsA/IL-2 indicated that CsA interfered with alloreactive NK cell-associated suppression of CTL activated by allogeneic tissue.
The ability of natural killer (NK) cells to recognize and reject transplants has so far been shown in hematopoietic grafts only. This study was designed to ascertain whether NK cells may also be involved in the rejection of transplanted organs. In most rat strain combinations, immunization with allogeneic cells induces a T cell response with cytotoxic T lymphocyte (CTL) activation. We have previously found one exception to this. In contrast to Wistar Furth rats (WF, RT1u), which manifest allospecific CTL activation in response to immunization with Brown Norway (BN, RT1n) cells, BN rats immunized with repeated intraperitoneal (i.p.) injections of allogeneic WF spleen cells manifest activation of alloreactive NK effector cells. The alloreactive NK cells were of the TCR-, CD3-, CD8+, and NKR-P1 intermediate phenotype and killed target cells with alloselectivity. In this study we used a heart transplantation model to study the rejection response of BN rats receiving WF grafts. NK cell infiltration was greater in WF hearts transplanted to BN recipients than in BN hearts transplanted to WF recipients. Furthermore, the extent of T cell infiltration was less in BN recipients. In WF rats transplanted with allogeneic BN hearts, CTL were activated in response to i.p. challenge with allogeneic BN cells, whereas BN rats transplanted with allogeneic WF hearts and i.p. challenged with allogeneic WF cells, manifested activation of alloreactive NK cells but no measurable activation of classic CTL. The alloreactive NK cells killed their allogeneic targets with specificity and with potency comparable to that of CTL. Furthermore, WF grafts were rejected in BN recipients as efficiently as were BN grafts in WF recipients. These results not only show cardiac allografts to be able to activate alloreactive NK cells, but also suggest that NK cells may be involved in the rejection of solid organ transplants and function as classic CTL in certain donor-recipient combinations.
BACKGROUND: With the increasing need for organ transplantation and the use of "marginal" organs, novel approaches are sought to increase the efficiency and survival of transplanted tissue. We tested the idea that treatment with the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous hormone that does not cause marked immunosuppression but does reduce reperfusion injury, may protect allografts and prolong their survival. METHODS: Donor cardiac grafts (Brown Norway) were transplanted heterotopically into the abdomen of recipient (Lewis) rats. Treatments consisted of intraperitoneal injections of Nle DPhe -alpha-MSH (NDP-alpha-MSH) or saline from the time of transplantation until sacrifice or spontaneous rejection. Allografts were removed on day 1, day 4, or at the time of rejection and examined for histopathology and expression of molecules prominent in reperfusion injury, transplant rejection, and apoptosis. RESULTS: NDP-alpha-MSH treatment caused a significant increase in allograft survival and a marked decrease in leukocyte infiltration. Expression of molecules such as endothelin 1, chemokines, and adhesion molecules, which are involved in allograft rejection, was significantly inhibited in NDP-alpha-MSH-treated rats. CONCLUSIONS: The results indicate that protection of the allograft from early injury with alpha-MSH can postpone rejection. Addition of this early protection with the peptide to usual treatment with immunosuppressive agents may, therefore, improve success of organ transplants.
This review documents the anaesthetic management, haemodynamic function and outcome in 18 of 86 heart-transplanted recipients, who returned for 32 non-cardiac surgical procedures at the Toronto Hospital from 1985 to 1990. General anaesthesia was administered in eight of the 27 elective operations and four of the five emergency operations. Induction medications included thiopentone (2-4 mg.kg-1), fentanyl (1-7 micrograms.kg-1) and succinylcholine (1-1.5 mg.kg-1). Anaesthesia was maintained with a combination of oxygen/nitrous oxide and isoflurane or enflurane. Muscle relaxation was maintained with vecuronium or pancuronium. No delayed awakening or unplanned postoperative ventilation was observed. Neurolept-anaesthesia was administered to 63.0% and 20.0% of the elective and emergency operations, respectively. The anaesthetics included fentanyl (25-100 micrograms) and midazolam (0.5-1.5 mg) or diazemuls (2.5-5.0 mg). Spinal anaesthesia (75 mg lidocaine) was administered to only two of the 27 elective operations. No important haemodynamic changes were observed in any anaesthetic group, but lower systolic BP was found after induction and during maintenance periods in the patients who received general anaesthesia than in those who received neurolept-anaesthesia. However, no anaesthesia-related morbidity or mortality was noted. This suggests that general, neurolept- and spinal anaesthesia do not affect haemodynamic function or postoperative outcome in heart-transplanted recipients undergoing subsequent non-cardiac surgery.
Comment In: Can J Anaesth. 1994 Jul;41(7):655-68087917
This study reviews the clinical outcome of the 132 orthotopic heart transplantations performed at our institute from 1984 through 1991 and focuses on the pathology of those patients who died. The study comprised 124 adults (mean age, 45.6 +/- 0.9 years) and eight children. Twenty-six adult and one pediatric deaths occurred. Operative mortality (within 30 days) was 10.6%, with 84.8% of patients surviving to discharge. Actuarial probabilities of survival at 1 and 5 years were 84% +/- 3% and 71% +/- 6%, respectively. Of the 27 deaths, six (22.2%) occurred in the operating room (from hemorrhage, graft failure, and hyperacute rejection); 14 (51.9%) occurred in-hospital after surgery (from sepsis, rejection, cytomegalovirus disease, or myocardial infarct), and seven (25.9%) occurred after discharge (from rejection and/or recurrent coronary artery disease). Two groups of patients were at higher risk: patients in cardiogenic shock requiring pretransplantation mechanical support, with in-hospital mortality of 39.1%; and patients with previous valve replacement who were taking oral anticoagulants, with intraoperative mortality of 50.0%. Pathologic examination revealed occasional instances of unsuspected coronary artery disease in the donor hearts with more than 50% stenoses of the left anterior descending coronary arteries in three of 21 (14.3%) of cases. Complications of the transplantation or related therapeutic procedures were common among those who died. The complications ranged from functionally insignificant anatomic curiosities to life-threatening problems. These complications are tabulated and shown.
Cardiac transplantation has become an established part of the therapy of end-stage heart disease. The number of cardiac transplants performed, as well as the number of centers performing them, has increased dramatically in the past 2 years. A paucity of literature on the anesthetic management of patients undergoing cardiac transplantation prompted this survey of 46 United States and Canadian institutions. The report summarizes the perioperative anesthetic management of a total of 1,273 transplant recipients in 34 institutions. Generally, similar anesthetic techniques and agents were used. One notable exception was the percentage of institutions using perioperative pulmonary artery catheter monitoring. As determined from this survey, right ventricular failure remains the leading cause of inability to terminate cardiopulmonary bypass in this patient population. Further, in surveyed institutions, cardiac transplantation expends more physician as well as hospital resources per patient than coronary artery bypass surgery.
The Seattle Heart Failure Model (SHFM) is 1 of the most widely used tools to predict survival in patients with heart failure. However, it does not accommodate very elderly patients. We decided to assess the applicability of the SHFM in patients >80 years old enrolled in a tertiary care heart failure clinic. We evaluated the difference between observed survival and mean life expectancy as predicted by the SHFM on 261 patients >80 years old enrolled in a heart failure clinic at the Jewish General Hospital, Montreal, Quebec, Canada from January 2002 through March 2010. Average age of the patient population was 85 ± 4 years (range 80 to 105). Sixty-two percent of the population consisted of men, 63% had ischemic cardiomyopathy (ICM), and average ejection fraction was 36 ± 18%. Median observed survival was 1.91 years (interquartile range 0.68 to 5.53) for the total population (n = 261). The SHFM (predicted median survival 6.7 years, interquartile range 3.8 to 11.2) overestimated life expectancy by an average of 4.79 years. For patients with ICM (n = 164) versus non-ICM (n = 97), the score overestimated survival by 4.29 versus 5.69 years, respectively. In conclusion, the SHFM overestimates life expectancy in elderly patients followed in a tertiary care heart failure clinic. Further studies are needed to more accurately estimate prognosis in this patient population.
Comment In: Am J Cardiol. 2013 Apr 15;111(8):123523558002