Effect of Cyclosporin A on the in Situ Inflammatory Response of Human Renal Allograft Rejection

Twenty cadaveric kidney allograft recipients were prerandomized into two groups. Ten patients (control group) were treated postoperatively with azathioprine (AZA) plus methylprednisolone (MP); the other ten received cyclosporin A (CyA) as the only immunosuppressive agent. Both groups received MP during rejection. One patient was excluded from the CyA group because of an early postoperative cardiac infarction and death. All transplants were monitored by alternate-day fine-needle aspiration biopsy and transplant aspiration cytology. Some patients treated with CyA had a significant initial decrease in urine output, reaching control values approximately 1 week postoperatively. The mechanism behind this deteriorated renal function is not clear, but it seemed to have been caused by injuries to the kidney tubular component, since a distinct monocytic-lymphocytic inflammation and severe cytological changes resembling pronounced acute tubular necrosis were observed concomitantly in transplant aspiration cytology. The CyA-treated patients had normal levels of blood leucocytes, thrombocytes and lymphocytes but displayed a strong early blood eosinophilia that was absent in the control subjects. During the first 30 days after transplantation 15 in situ episodes of inflammation were recorded in the nine transplants treated with CyA, whereas only 6 episodes were found in the 10 transplants receiving AZA + MP (P<0.01). The first inflammatory episode in the CyA-treated transplants peaked between days 5 and 8 after transplantation and was followed by another distinct inflammatory episode between days 23 and 26. In the AZA- plus MP-treated transplants, only one inflammation episode was observed, with a peak on day 14 postoperatively. The inflammatory cell types most prominently present in the CyA-treated transplants were lymphocytes, B plasmablasts and monocytes. The early inflammatory episodes in the CyA-treated transplants may have been related to the fact that during the initial intramuscular administration, therapeutic CyA concentrations in patient serum were not achieved until the fourth postoperative day during peroral administration. The onset of transplant function had no impact on the in situ inflammatory response of rejection in the CyA-treated transplants or on the concentration of CyA in patient serum. This indicates that CyA may also be used in initially non functioning transplants. Confirming our earlier results, we were unable to demonstrate the major histocompatibility complex (MHC) antigens on the healthy grafts treated with AZA plus MP. However, in healthy allografts treated with CyA, both classes of MHC antigens were nearly invariably demonstrable on the graft endothelial cell surface. Approximately 60% allograft survivals were recorded in both groups at 6 months, and all patients with functioning grafts were able to work.     

Bone marrow transplantation in Batten disease (Neuronal ceroid-lipofuscinosis). Will it work? Preliminary studies on coculture experiments and on bone marrow transplant in late infantile Batten disease

Lymphocytes from a patient with preclinical late infantile Batten disease were cultured alone and with lymphocytes from donors, and the fate of the curvilinear inclusions characteristic of the disease was monitored by electron microscopy. There was no evidence of transfer of deficient enzyme or factor that might have caused removal of the stored material, and the curvilinear profiles remained in the cultured cells without signs of degradation. Cells stimulated to divide with phytohaemaglutinin did not exhibit storage in culture suggesting that storage is a function of the age of the cell. The patient received a bone marrow transplant at 2 7/12 years while still clinically unaffected, and the effect on lymphocytes and cells in skin and rectal biopsies was monitored by electron microscopy over a period of 9 months until the donor marrow became displaced by the host cells. He has had one seizure and now has neurophysiological evidence of late infantile Batten's disease. Bone marrow transplant may have no effect on material already stored but might prevent further build-up and halt the onset of the clinical symptoms although very recent studies on early (fetal) transplants in sheep with a form of Batten disease have shown no benefit. © 1995 Wiley-Liss, Inc.     

Correction of DiGeorge anomaly with EBV-induced lymphoma by transplantation of organ-cultured thymus and Epstein-Barr-specific cytotoxic T lymphocytes

A young woman with DiGeorge anomaly showed normal immune tests as a child and did not experience the symptoms of profound T cell immunodeficiency. However, she had chronic pulmonary infections which led to bronchiectasis. At age 14, she developed an Epstein-Barr virus-induced lymphoma and her T cell function tests were markedly abnormal. After intensive chemotherapy, she received an organ-cultured thymus transplant but because of an abnormally high EBV DNA titer was also given autologous EBV-specific cytotoxic T cells, prepared prior to transplant. Titers fell from 80,000 genome copies/mg DNA to 2000 within 6 weeks. She was clinically well and her T cell tests improved. Sixteen months after the transplant, however, her tumor returned; EBV DNA levels had risen to 40,000 copies/mg DNA. She again received autologous EBV-specific cytotoxic T lymphocytes and valcyclovir and Cytogam as well. Her tumor resolved on this therapy and she has remained well to this date, 29 months after the recurrence. T cell tests, which had deteriorated with the recurrence of the tumor, now show normal responses. This experience records a number of unique features of thymus transplantation. This is the first recorded successful thymus transplant in a patient with partial T cell immunity and thus expands the potential of this treatment modality to patients other than infants with complete DiGeorge anomaly. The patient demonstrates cytotoxic activity against mouse cells, demonstrating the ability to respond to a new antigen which requires host antigen presenting cells. Measurement of alpha 1 TRECs (T cell receptor excision circles) shows evidence of increasing and sustained thymopoiesis since the transplant at a level consistent with the age of the transplant donor rather than that of the recipient.     

The pathological implications of heart transplantation: Experience with 50 cases in a single center

Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post‐transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post‐transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post‐transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody‐mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10‐year survival rate is due to donor evaluation and post‐transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results.     

Successful bone marrow transplantation in a patient with humoral and cellular immunity deficiency

An immunity deficiency disease occurring in three siblings is described. Two siblings, a boy and a girl, died at ages 1½ years and 4½ years respectively with overwhelming varicells, varicella pneumonia and sepsis. Their disease included thymic hypoplasia, lymphopenia, deficient humoral and cellular immunity, absent serum IgA, neutropenia and eosinophilia.

Transplantation of bone marrow, identical by cytotoxic and mixed leucocyte assay, red cell antigens and Gm and Inv factors was given to an affected girl from a normal sibling on two occasions. The first transplant given at 6 months of age resulted in clinical improvement of the patient and some evidence of immunologic reconstitution. Complete correction of the immunity defect was achieved following a second bone marrow transplant at 11 months of age. A delayed onset and prolonged course of GVH reaction was observed following the second transplant. The patient survived the GVH without specific therapy. Evidence for complete immunologic reconstitution continued to be present 1 year following the second transplantation.

     

In-utero transplantation of fetal liver stem cells into human fetuses.

Three human fetuses were treated by transplantation of human fetal liver stem cells. Two of them had severe immunodeficiency disease and the third had thalassaemia major. All three in-utero transplants were followed by engraftment. No adverse effect was seen. The three patients have now been born: the first is very healthy thanks to the reconstitution of cell-mediated immunity associated with this transplant, and he lives normally at home; the other two, who were treated more recently, have not yet shown a complete effect. The feasibility and efficacy of this procedure, used for the first time in humans, has therefore been demonstrated: during early fetal development, foreign cells engraft readily and may result in significant improvement of a large variety of inherited diseases.     

Abnormal B-cell proliferation associated with combined immunodeficiency, cytomegalovirus, and cultured thymus grafts

A male infant in whom multiple recurrent multiorgan infections developed during the first six months of life was found to have combined immunodeficiency. Progressive pulmonary disease developed at age two years; cytomegalovirus (CMV) was isolated from the respiratory tract and urine. Three separate intramuscular grafts of cultured thymus fragments did not produce change in the course of the illness. Soon after age three years, IgG lambda appeared in the serum as an M-component. The patient died at age three and one-half years, with respiratory insufficiency due to pulmonary fibrosis. At autopsy, a malignant plasma cell infiltrate was limited to the retroperitoneum. The infiltrate replaced lymph node structures and surrounded nerve fascicles, which appeared necrotic, and contained CMV inclusions in ganglion cell nuclei. The plasma cells showed strong monoclonal staining for IgG lambda. Also noted was positive staining for J-chain, which has been reported previously in malignant plasma cells producing IgG. CMV could be responsible for abnormal B-cell proliferation in patients with defective immunoregulation who receive immunotherapy, as in lymphoid abnormalities associated with Epstein-Barr virus.     

Tolerance maintenance depends on persistence of the tolerizing antigen: evidence from transplantation studies on Xenopus laevis

In order to assess the role of antigen persistence in the tolerant state, tolerance was induced in Xenopus laevis by the embryonic transplantation of whole eyes or tail tissue. Both types of transplants were seen to heal in and persist, with no signs of immunological incompatibility. At metamorphosis, tail resorption occurred and grafted tail tissue was lost. Eye transplants were maintained through metamorphosis in most eye grafted animals. Eye graft recipients which had maintained the transplant were observed to accept challenge skin allografts from donors of the same genotype as the eye donor in all but one case, while recipients which had lost the eye transplant at metamorphosis or had the eye transplant experimentally removed sometimes did not accept the challenge skin graft. Animals tail grafted as embryos did not accept post metamorphic skin grafts from donors of the same genotype as the tail tissue donor, but rejection was not accelerated. It is proposed that tolerance induction is dependent on the presence of appropriately presented antigen at a time when precursor thymocyte cells are migrating to the thymus, prior to their processing into alloreactive cells, and that tolerance maintenance is dependent upon the persistence of the tolerizing antigen.     

Stem cell transplants for patients with X-linked agammaglobulinemia

Six young patients with X-linked agammaglobulinemia and proven mutations in Btk were treated with cord blood or bone marrow transplants from HLA-matched siblings. Complete blood counts, serum chemistries, serum immunoglobulin concentrations, lymphocyte cell surface markers, and physical findings were evaluated at 3- to 5-day intervals for the first 2 weeks after transplant and then every 3 to 6 months. The first three patients were not given any preparative regimen or antirejection drugs and at 24 to 42 months posttransplant these patients have shown no benefit or harm related to the transplants. The second three patients were not given a preparative regimen but were treated with cyclosporine A (70 days) and mycophenolate mophetil (28 days) after transplant. Two of these patients have developed normal sized, nontender cervical lymph nodes 3 to 12 months after transplant but none of the three patients have shown an increase in serum IgM or an increase in the number of peripheral blood B cells. It is likely that successful engraftment will require more aggressive immunosupressive medications.     

Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease.

BACKGROUND. Parkinson's disease is characterized by the loss of midbrain dopamine neurons that innervate the caudate and the putamen. Studies in animals suggest that fetal dopaminergic neurons can survive transplantation and restore neurologic function. This report compares the clinical results in four case patients with severe Parkinson's disease who underwent stereotaxic implantation of human fetal ventral mesencephalic tissue in one caudate nucleus with the results in a control group of similar subjects assigned at random to a one-year delay in surgery. METHODS. Each case patient received cryopreserved tissue from one fetal cadaver (gestational age, 7 to 11 weeks). Before implantation, adjacent midbrain tissue underwent microbiologic, biochemical, and viability testing. Cyclosporine was administered for six months postoperatively. RESULTS. The procedure was well tolerated. Three case patients showed bilateral improvement on motor tasks, as assessed on videotape, and were more functional in the activities of daily living, as assessed by themselves and neurologists, during both optimal drug therapy and "drug holiday" periods. One case patient, who died after four months from continued disease progression, had striatonigral degeneration at autopsy. In the patients who received transplants, optimal control was achieved with a lower dose of antiparkinsonian medications, whereas the controls required more medication. Positron-emission tomography with [18F]fluorodopa before and after surgery in one patient revealed a bilateral restoration of caudate dopamine synthesis to the range of normal controls, but continued bilateral deficits in the putamen. CONCLUSIONS. Although the case patients continued to be disabled by their disease, unilateral intracaudate grafts of fetal tissue containing dopamine diminished the symptoms and signs of parkinsonism during 18 months of evaluation.     

Severe combined immune deficiency presenting with cyclic hematopoiesis

At age 2 months a male infant presented with a cyclic clinical syndrome every 14–21 days that included pharyngeal aphthous ulcers, high fever, lymphadenopathy, pallor, and malaise. Serial blood studies indicated cycling of all blood cell elements, compatible with a diagnosis of cyclic hematopoiesis (CH). He also manifested a progressively severe immune deficiency, not described before in human CH. When first studied at age 5 months, he was hypogammaglobulinaemic with normal B lymphocyte numbers. By 6.5 months, he was agammaglobulinaemic. At age 8 months, he developed severe pneumocystis carinii pneumonia, and studies showed a state of severe combined immune deficiency. The patient received a bone marrow transplant from his HLA-identical sister with no preconditioning therapy. Subsequently, normal immune function developed and the cyclic hematopoiesis resolved. The majority of lymphocytes is of donor origin. Persistence of erythrocytes and neutrophils of recipient origin suggests that the hematopoietic stem cells were not abnormal. We speculate that this patient had a primary deficiency of a differentiation factor affecting maturation of lymphoid and myeloid progenitor cells.     

Emulation of seizure induced brain damage in neural tissue transplants to the anterior chamber of the eye

Summary We have developed a model system in which the mechanisms of neuronal damage due to hyperexcitation can be studied in isolation and where extended observation periods can be used. Substantia nigra pars reticulata (SNPR) develops a hypermetabolic necrosis following status epilepticus (Nevander et al. 1985; Auer et al. 1986). We transplanted rat fetal nigral area alone or together with fetal frontal neocortex to the anterior chamber of the eye in adult rats. Following 3 months of transplant maturation the hosts were subjected to status epilepticus for 60 min. In single nigral transplants no sign of structural damage was found. In the double transplants of frontal cortex and the substantia nigra a tissue necrosis had developed in the nigral part. This was demonstrated by a total loss of glial fibrillary acidic protein (GFA) immunoreactivity within a circumscribed necrotic region in the nigral part of the double transplant. Such a loss of GFA immunofluorescence had also developed in the host SNPR, as we have earlier shown (Eriksdotter Nilsson et al. 1987). Thus, intraocular brain tissue transplants provide a unique model for studies on the development of neuronal damage and functional dependence between different neuronal structures for the development of such damage.Abbreviations SNPR Substantia nigra pars reticulata - SN Substantia nigra     

Tumor embolism as a cause of an unexpected death: a case report

The primary causes of deaths for individuals with rare cancers can be difficult to diagnose clinically. Often, the symptoms implicate a variety of factors, and an autopsy is thus required to obtain the correct diagnosis. This study analyzes the death of a 45-year-old woman who reportedly died from an acute pulmonary dysfunction. The patient had been treated with antibiotics for three months for intractable pneumonia. Suspicious coin lesions detected by chest X-ray prompted a clinical clarification; however, no final diagnosis was made. The autopsy revealed a bulky thyroid tumor with venous invasion, leading to a massive pulmonary tumor embolism. Furthermore, microscopy identified the tumor as a rare pleomorphic myxoid sarcoma. Thus, the patient died of a large pulmonary tumor embolism originating from this rare sarcoma, and not of acute pulmonary dysfunction of any other means.     

Absence of adrenal influence on ovarian graft activity in male rats castrated at birth

1. An investigation was made to see whether the presence of the adrenal gland was necessary for cyclical activity of ovarian transplants in adult male rats which had been castrated at birth.2. Rats were castrated on the day of birth or at 6-8 weeks of age and when 3 months old were adrenalectomized and had a transplant of immature ovary placed in the anterior chamber of one eye. Control animals were subjected to the same procedure apart from adrenalectomy.3. Transplants in rats castrated at birth were observed to undergo full cyclical activity, with follicular rupture and the formation of corpora lutea. Transplants in rats castrated at 6-8 weeks of age did not cycle and corpora lutea were not formed.4. Adrenalectomy did not influence the behaviour of the ovarian transplants.5. It is concluded that the presence of the adrenal gland was not necessary to support cyclical activity in ovarian tissue transplants in male rats castrated at birth.     

Circulating thymic hormone levels in severe combined immunodeficiency.

Twenty-three patients with severe combined immunodeficiency disease were studied for circulating thymic hormone levels (facteur thymique serique, FTS), 21 prior to treatment by transplantation of bone marrow, thymus or fetal liver. Thirteen showed undetectable FTS activity. Only two had normal levels of this hormone. In serial determinations of FTS activity prior to and after transplantation, patients given bone marrow transplants developed sustained increments of serum FTS activity early in the course of their immunological reconstitution. However, patients given transplants of fetal liver alone or fetal liver plus thymus from fetuses of less than 12 weeks gestation generally did not show an increment of FTS activity during the period of observation. Transplantation of irradiated thymus derived from fetuses of more than 14 weeks gestation produced sustained increases of thymic hormone activity. These observations suggest that a cell of haematopoietic origin provides a stimulus necessary for differentiation or maturation of thymic secretory activity and that this cell(s) is present in post-natal marrow, but is either undeveloped or immature in the early fetal liver or fails to migrate to the thymus of an allogeneic host.     

Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) with methylprednisone and oxymethalone in aplastic anaemia

From 1986 to 1994 we treated 26 patients of aplastic anaemia between 6 to 61 years age group with ATG/ALG, Methylprednisone and Oxymethalone. Five had very severe aplastic anaemia, 16 had severe and 5 nonsevere disease. Disease was associated with hepatitis in 5 patients and with pregnancy and drug use in 2 patients each. In others no cause could be ascertained. A total of 31 courses of treatment were given (range 1-3 courses per patient). Nine patients had complete response (34.62%) and 3 had partial response (11.54%) with an overall response rate of 46.16%. Four patients died within 2 months of starting the treatment. The median follow up was 24 months (range 6-102 months) with an overall survival probality of 45% at 2 yr. At the time of evaluation 12 patients have died, 9 are alive disease-free and 5 are alive with disease. The side effects associated with therapy were tolerable and did not require cessation of therapy in any patient. We conclude that ATG/ALG with Methylprednisone and Oxymethalone is beneficial to significant number of patients with aplastic anaemia.     

Multiple changes in noradrenergic mechanisms in the coeruleo-hippocampal pathway during aging. Structural and functional correlates in intraocular double grafts

Age-related changes of the coeruleo-hippocampal noradrenergic system were investigated using intraocular double transplants. Pieces of fetal hippocampus were grafted into the anterior chamber of the eye and placed into contact with previously inserted locus coeruleus grafts. Ages of both transplants and hosts were varied to enable studies of intrinsic versus extrinsic determinants of aging in an isolated neuronal circuit. Four different experimental groups, with the approximate age in months of grafts/hosts at the time of recording given in parentheses, were studied; young grafts in the eyes of young hosts (3/7), young grafts in the eyes of old hosts (3/23), mature transplants in adult host rats (8/12) and aged transplants in the eyes of aged rats (21/25). Extracellular recordings from the hippocampal part of the double grafts were performed. Superfusion with alpha-adrenergic antagonists and the alpha 2-agonist clonidine elicited significant increases in the discharge rate of the grafted hippocampal neurons in all groups except the aged transplants in the aged hosts (21/25), where a small excitation was elicited with clonidine and no effect at all was seen with alpha-adrenergic antagonists. The host age did not seem to be important since young transplants in the old hosts (3/23) showed a similar increase in discharge rate as transplants in the young and adult hosts. Tyrosine hydroxylase immunohistochemistry and high-performance liquid chromatography revealed that hippocampal transplants remaining in oculo for a minimum of 6-10 months became permanently hyperinnervated by noradrenergic fibers from the locus coeruleus grafts. The density of noradrenergic fibers was significantly lower in young transplants.(ABSTRACT TRUNCATED AT 250 WORDS)     

复方磺胺甲恶唑对肾移植后卡氏肺孢子虫肺炎的预防作用

背景：卡氏肺孢子虫肺炎是由卡氏肺孢子虫寄生于肺部引起的一种严重的致命性肺炎。复方磺胺甲恶唑是目前用于治疗卡氏肺孢子虫肺炎的一线药物,治疗量往往有明显的不良反应,小剂量预防用药临床疗效及毒副作用尚不清楚。 目的：观察复方磺胺甲恶唑对肾移植后卡氏肺孢子虫肺炎的预防效果。 方法：选择肾移植后1个月且无复方磺胺甲恶唑过敏者。肾移植后1个月至半年或1年常规服用复方磺胺甲恶唑(0.48 g/d)。观察移植肝肾功能,感染情况,药物不良反应。 结果与结论：2006年起,随访125例肾移植术后早期患者,73例术后1个月起常规服用复方磺胺甲恶唑(0.48 g/d)至术后半年者,1例停药4个月后感染卡氏肺孢子虫肺炎死亡,47例服用复方磺胺甲恶唑(0.48 g/d)至术后1年者,无感染卡氏肺孢子虫肺炎者,5例因复方磺胺甲恶唑过敏或医从性差未服用复方磺胺甲恶唑者,2例分别在术后4,5个月感染卡氏肺孢子虫肺炎,1例死亡。结果提示,肾移植术后1个月至1年常规服用复方磺胺甲恶唑(0.48 g/d),可有效预防卡氏肺孢子虫肺炎,临床无明显不良反应。     

Pediatric heart transplantation after declaration of cardiocirculatory death

In three infants awaiting orthotopic cardiac transplantation, transplantation was successfully performed with the use of organs from donors who had died from cardiocirculatory causes. The three recipients had blood group O and were in the highest-risk waiting-list category. The mean age of donors was 3.7 days, and the mean time to death after withdrawal from life support was 18.3 minutes. The 6-month survival rate was 100% for the 3 transplant recipients and 84% for 17 control infants who received transplants procured through standard organ donation. The mean number of rejection episodes among the three infants during the first 6 months after surgery was 0.3 per patient, as compared with 0.4 per patient among the controls. Echocardiographic measures of ventricular size and function at 6 months were similar among the three infants and the controls (left ventricular shortening fraction, 43.6% and 44.9%, respectively; P=0.73). No late deaths (within 3.5 years) have occurred in the three infants, and they have had functional and immunologic outcomes similar to those of controls. Mortality while awaiting a transplant is an order of magnitude higher in infants than in adults, and donors who died from cardiocirculatory causes offer an opportunity to decrease this waiting-list mortality.     

Alpers progressive infantile neuronal poliodystrophy: An acute neonatal form with findings of the fetal akinesia syndrome

We report on 8 patients from two families with Alpers syndrome. The onset in one family was prenatal and in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity were found. The second family presented with an early infantile form. All the effected offspring had micrognathia and one had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all the patients died before age 20 months. Results of comprehensive biochemical and metabolic studies in both families were normal and the diagnosis was supported by demonstration of extensive progressive brain atrophy on CT and typical histological findings. Patients without a detectable defect in energy metabolism and normal liver histology comprise a distinct subset of Alpers syndrome. Until the metabolic defect(s) is defined, we suggest naming the acute neonatal form of this subset of Alpers syndrome “type 1.”. © 1993 Wiley-Liss, Inc.