Morphological findings in kidney transplants before and after late conversion from cyclosporine A to azathioprine.
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Biomedical subjects
Publications and source records attributed to J Jeekel.
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The effect of cytomegalovirus (CMV) disease on mononuclear subpopulations of 49 renal transplant recipients treated with cyclosporine and prednisone are reported. Clinical overt CMV infection developed in 8/21 patients treated for rejection with rabbit antithymocyte globulin. They all showed true inversions of the T helper/T suppressor-cytotoxic (Th/Ts-c) ratio. A reduction of T helper cells and increase in T suppressor-cytotoxic cells preceded clinical symptoms of CMV disease by one week. None of the 26 patients without RATG anti-rejection treatment developed CMV disease and in only three of them an inversion of Th/Ts-c ratio was found.
A total of 20 patients with advanced colorectal cancer received recombinant leukocyte interferon-alpha A (rIFN alpha A) either chronically (group I: twice a week up to 20 X 10(6) IU/m2 i.m.) or cyclically (group II: 1-4 periods of 8 consecutive days up to 20 X 10(6) IU/m2 i.m. daily at 20-days intervals) over a period of 12 weeks. There was 1 partial response, 1 mixed response and 1 patient with stable disease, whilst 17 patients had progressive disease. Median survival was 15.5 months. Survival was significantly shorter when the extent of hepatic disease was greater than 25% (P = 0.05), extrahepatic disease was extensive (P less than 0.005), alkaline phosphatase level was greater than 2 X normal (P less than 0.02), or performance status was less than 100% (P less than 0.001). Toxicity consisting mainly of fever, fatigue, anorexia and weight loss was serious in group I and minimal in group II. Administration of rIFN alpha A led to a "short lived" augmentation of natural killer (NK) cell activity. In the cyclically treated group this was a recurrent phenomenon whereas a marked lasting depression of NK cell activity was seen in chronically treated patients. Interferon-gamma production capacity was significantly stimulated during rIFN alpha A therapy. The differences in toxicity and immunostimulatory effects between the two schedules may be of importance in the design of further studies.
ABPP (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a pyrimidinone with known interferon-inducing, natural killer (NK) cell activity enhancing, antiviral and antitumor properties in several animal species. Its effect on CC531, a dimethylhydrazine-induced, transplantable, weakly immunogenic adenocarcinoma of the colon in WAG rats, was studied. ABPP was found to have no direct cytotoxic effect on CC531 cells in vitro. When small cubes of tumor of equal weight were implanted under the renal capsule, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 led repeatedly to significant (p less than 0.02 up to p less than 0.001) inhibition of tumor growth, when measured on day +7. Lower doses or a single dose of ABPP did not achieve this effect. Late administration (on day +6 and +7) of 250 mg/kg of ABPP in this model was found to have no effect on tumor growth when measured on day +13. When 5 X 10(5) tumor cells were injected in the portal vein, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 reduced significantly (p = 0.002) the number of liver metastases, when counted on day +30. Survival in this group was significantly prolonged (p less than 0.01). However when ABPP was given on day +6 and +7, significantly more (p less than 0.02) metastases in the liver were counted on day +30. The results show a significant antitumor effect of ABPP against tumor CC531 in the subrenal capsule assay (SRCA) model as well as in the liver metastasis model when administered at the time of tumor inoculation. Late administration of ABPP did not inhibit tumor growth in the SRCA and significantly enhanced the development of liver metastases. The role of timing, tumor site, and the mechanisms by which this dual outcome of immunotherapy with ABPP is mediated are discussed. The results of these experiments may have important implications for the design of clinical studies with ABPP.
The effect of a single blood transfusion on the formation and outgrowth of experimental lung metastases was assessed in two tumor models in rats. The transfusions were given either 1 week before (day -7) or 1 week after (day +7) tumor cell inoculation. The first approach was performed to investigate the effect of transfusions on the formation of lung colonies, the second approach to study the effect on the outgrowth of established metastases. The first tumor model used was a transplantable, nonimmunogenic sarcoma (LS175) in BN rats. Animals were injected i.v. with 10(5) tumor cells and the number of metastases developing in the lungs was counted after 18 days. Experimental animals received 1 ml of allogeneic WAG blood, controls were given 1 ml of syngeneic BN blood. A single allogeneic transfusion given on day -7 had no effect on the formation of LS175 lung colonies but, when given day +7, stimulated the outgrowth of established metastases. The second tumor model was a highly immunogenic transplantable basal cell carcinoma (BC1618) in inbred WAG rats. Rats were injected i.v. with 10(6) tumor cells and the numbers of lung colonies were counted after 21 days. Experimental animals were transfused with 1 ml of BN blood, controls received 1 ml of WAG blood. An allogeneic transfusion on day -7 led to a significant inhibition of lung metastases, whereas a transfusion on day +7 had no effect. The results clearly indicate that allogeneic blood transfusions can modulate tumor growth and metastasis. Although immunological factors seem to play a crucial role in this transfusion phenomenon, there was no clear-cut correlation between the observed effects (accelerated tumor growth vs inhibition of metastasis) and the type of immunomodulation evoked.
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A technique for auxiliary heterotopic transplantation of 60% of the liver has been developed in the pig to study acute and chronic rejection. Transplantations were performed in 13 non-tissue-typed donor-recipient combinations without immunosuppressive medication. Three pigs died in the 1st postoperative week from technical problems. In the remaining 10 animals acute rejection of the graft was not found, but signs of chronic rejection developed in 6 animals. It is concluded that auxiliary partial liver transplantation is technically feasible in the pig. Although the auxiliary liver graft is subject to immune attack, long-term graft survival without immunosuppressive medication can be achieved.
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Lymphomas occurring in renal transplant recipients are mostly large cell non-Hodgkin's lymphomas (B-cell-derived). A sarcoma with all morphologic, immunohistochemical, and ultrastructural characteristics of a tumor of the mononuclear phagocytic system (MPS) developed in a 23-year-old woman 1 year after renal transplantation. Anti-Epstein-Barr-virus antibody titers proved to be exceptionally high, even in pretransplant sera. Tumor-derived cells proved to be positive for Epstein-Barr nuclear antigen (EBNA), and hybridization showed multiple copies of Epstein-Barr virus (EBV)-DNA, suggesting a relationship between this tumor and EBV. More widespread use of immunochemical and histochemical diagnostic techniques might detect more cases, which, until now, have probably been diagnosed as B-cell-derived immunoblastic lymphomas.
Ultrasound-guided percutaneous transhepatic cholecystostomy was performed in six critically ill patients who had acute acalculous cholecystitis. The clinical conditions of all six patients improved dramatically following transhepatic cholecystostomy. No complications of this bedside procedure occurred. Cholangiography via the inserted pigtail catheter was normal in four patients. Their catheters were removed after ten to 21 days. At follow-up examinations at four to 30 months they were free of signs of gallbladder disease. In one patient, ultrasonography showed desquamation of the mucosa in the gallbladder, which led to the decision to perform cholecystectomy two days after cholecystostomy. One patient, suffering from cholangiocarcinoma, died 120 days after cholecystostomy with the catheter in situ. In our experience, ultrasound-guided percutaneous transhepatic cholecystostomy is the treatment of choice to overcome a critical period in patients with acute acalculous cholecystitis. When post-drainage cholangiography is normal, cholecystectomy at a later stage is not indicated in the majority of these patients.
The combined effect of 5-Fluorouracil (5-Fu) and partially purified rat interferon (RIFN) was assessed on experimental liver metastases of a transplantable colon tumor in rats. Treatment was given for 8 weeks and started 1 week after inoculation into the portal vein of 5 X 10(5) tumor cells. Administration of 10(5) units RIFN/kg/day for 7 days, in alternate weeks, had no effect on the number or size of liver metastases as judged by laparotomy on days 30 and 50, whereas treatment with 5-Fu at a dose of 15 mg/kg once a week had a moderate but significant inhibitory influence. The combined administration of RIFN and 5-Fu led to earlier development of liver metastases than in the control group. There was no difference in survival time between the control group and the RIFN-treated group; all animals died within 20 weeks after tumor cell injection. However, three of eight animals in the 5-Fu group and, surprisingly, four of ten animals in the RIFN + 5-Fu group survived for more than 20 weeks and were found to be free of tumor when inspected after 175 days. The data indicate that 5-Fu, given either alone or combined with RIFN, is effective in about 40% of cases, and further suggest that RIFN has tumor-enhancing properties in those animals in which treatment with 5-Fu has no antitumor effect.