HLA-restricted cytotoxicity against male-specific (H-Y) antigen after acute rejection of an HLA-identical sibling kidney: clonal distribution of the cytotoxic cells.

A 22-year-old previously nonsensitized female patient (HLA-A2,28; B7,14; DR1,2) received a kidney from her HLA-identical brother. She irreversibly rejected the graft 2 1/2 weeks later. In vitro tests performed 6 weeks after the graft loss, using recipient responding and donor-stimulating and target cells, revealed a weak mixed lymphocyte culture (MLC) response and negative direct cell-mediated lympholysis (CML), but strong cytotoxicity against donor target cells after priming in MLC. Both MLC and CML tests using donor-responding cells and recipient-stimulating and target cells were negative. When the patient's cytotoxic cells were tested on a panel of target cells from nonrelated donors, a significant CML was only found against target cells from male donors sharing HLA-A2 and/or B7 with the patient, not with male target cells sharing A28 or B14. By using cold target inhibition tests, two separate populations of male-specific cytotoxic cells could be demonstrated. The one was restricted by HLA-A2, the other by B7. These findings indicate that a self-HLA-restricted cytotoxicity against a male-specific minor histocompatibility antigen was a major cause of the rejection in this case.

Cell-mediated cytotoxicity toward the donor in patients with well-functioning kidney grafts. Possible mechanism of specifically reduced cytotoxic response.

Patients with well-functioning kidney allografts from one-HLA-haplotype--mismatched related donors have strongly reduced donor-specific cell-mediated cytotoxicity 2-10 years after having received their grafts. This could also be demonstrated in secondary in vitro cell-mediated lympholysis (CML). Even though secondary donor-specific CML did not exceed 10% at an effector-to-target cell ratio of 50:1, specific lysis of donor target cells increased significantly with increasing effector cell concentrations. The weak cytotoxicity toward the donor could be enhanced neither through pool-cell stimulation nor by adding exogenous Interleukin 2 (IL-2) during the induction phase. Furthermore, growth factors were produced in the cultures during the induction of cytotoxic cells in concentrations comparable to those of the sibling control. Thus no evidence could be obtained that lack of IL-2 was causing the decreased cytotoxicity in these patients. Our studies indicate that in vivo depletion of cytotoxic cells with high lytic efficiency is probably the reason for the strongly reduced donor-specific cytotoxicity.

Donor-specific decreased cell-mediated cytotoxicity in recipients of well functioning, one HLA haplotype-mismatched kidney allografts.

Patients with well functioning kidney grafts from one HLA haplotype-mismatched related donors were studied 2 to 10 years after transplantation. No direct cell-mediated lympholysis (CML) toward donor cells was found. After in vitro sensitization in mixed lymphocyte culture, the recipient effector cells were not able to significantly kill donor target cells at an effector to target cell ratio of 50:1, while the HLA-A,B,D/DR-identical sibling of the recipient could generate strong cytotoxicity toward the donor at similar effector to target cell ratios. Nevertheless, the patient developed strong cytotoxicity toward third-party targets. Our findings indicate in vivo depletion of cytotoxic cells with specificity for donor antigens. No correlation between the mixed lymphocyte culture (MLC) response and the ability to generate cytotoxic cells could be found in recipient-donor combinations. In looking for in vivo generated suppressor cells toward the donor, a moderate suppression was found in three of six patients studied.

Cytotoxic T cells recognizing minor transplantation antigens, and possibly a variant of the HLA-B8 molecule. Cause of rejection of an HLA-identical sibling kidney transplant?

A male uremic patient was first transplanted with a kidney from a female cadaveric donor. The kidney was rejected after two weeks. He was retransplanted approximately one year later with a kidney from his HLA-identical sister. This graft was also irreversibly rejected after one week. No serum antibodies could be detected against the sibling donor before or after transplantation, but the recipient had formed donor-specific cytotoxic T lymphocytes (CTLs). The CTLs were cloned, and clones with two different specificities were obtained. One clone lysed target cells from the donor, from some other family members, and from 50% of a panel sharing HLA-B15 with the recipient. It may recognize a minor transplantation antigen, that is restricted by HLA-B15. The other clone lysed target cells from the donor, from all HLA-B8-positive family members (except the recipient), and from third-party cell donors sharing HLA-B8 with the recipient. When CTLs from third-party individuals were induced toward HLA-B8, target cells from all HLA-B8-positive family members were lysed, except those from the recipient. This indicates that the recipient may have inherited a variant of HLA-B8 that is not detectable by antibodies but by CTLs. These donor-specific CTLs may have contributed to the rejection of the HLA-identical sibling transplant.

A Scandinavian two-center study of BMA 031 in steroid-resistant rejection of renal grafts.

BMA 031 (Behring Monoclonal Antibody) was given to 25 renal graft recipients with biopsy-proven steroid-resistant rejections. A dose of 50 mg of BMA 031 was given i.v. on 7 consecutive days concomitantly with a standard triple-drug regimen. No premedication was administered before the first BMA 031 dose. After the first dose, 7 patients experienced moderate fever (< 39 degrees C), 5 patients had high fever (> 39 degrees C), 4 patients had nausea/vomiting, 3 diarrhea, 1 headache, and 1 hypertension. These reactions were seen only after the first dose except for 1 patient who developed urticaria on days 3-4. All the rejection episodes were reversed or partially reversed. Twenty-one patients experienced re-rejections 3-46 days after the last BMA 031 dose, and were treated with methylprednisolone and/or rabbit antihuman thymocyte globulin. Seven patients lost their grafts within 1 year (28%), including 2 patients who died of infection with a functioning graft. BMA 031 seems to be a safe drug with only few mild side effects, and it effectively reverses steroid-resistant rejections. Re-rejections were frequent, but mostly reversible.

Technetium-99m-tetrofosmin for parathyroid scintigraphy: a comparison with sestamibi.

UNLABELLED: Parathyroid scintigraphy with the new myocardial perfusion radiopharmaceutical 99mTc-tetrofosmin was compared with 99mTc-sestamibi scintigraphy using early and delayed imaging. METHODS: The two preparations were administered on different days to the same 16 patients suffering from primary hyperparathyroidism. Anterior view gamma camera planar imaging (10-min acquisition) was performed in the period between 5 min and 3 hr after administration of the radiopharmaceutical. For most of the patients, a pertechnetate image of the thyroid was available for eyeball comparison when reading the tetrofosmin and sestamibi images. Imaging results were compared with those from histopathological examination after surgery. RESULTS: On early images, all the adenomas visualized with sestamibi were equally well seen with tetrofosmin and vice versa. In 6 of 11 scintigraphically detected neck adenomas, delayed imaging improved the adenoma visualization with sestamibi. In contrast, this differential washout was never seen with tetrofosmin. Histopathological examination of excised tissue specimens after neck exploration (15 patients) or thoracotomy (one patient) revealed a parathyroid adenoma in all 16 patients. Our 12 scintigraphic findings were true-positives, while the remaining four scintigraphies were false-negatives, giving a diagnostic sensitivity of 75% with both preparations. The mediastinal adenoma was detected in a patient with a history of two unsuccessful neck explorations and one unsuccessful thoracotomy. CONCLUSION: Tetrofosmin has the same success rate as sestamibi for detection of parathyroid adenomas on scintigrams acquired immediately after injection. In contrast to sestamibi, delayed imaging has no diagnostic impact. Moreover, the thyroid/ parathyroid differential washout of sestamibi failed in 5 of 11 neck adenomas here detected, indicating that delayed sestamibi washout is an unreliable diagnostic criterion. Therefore, whether sestamibi or tetrofosmin is preferred for parathyroid scintigraphy, thyroid scintigraphy seems mandatory.

Laparoscopic and open surgery for pheochromocytoma.

BACKGROUND: Laparoscopic adrenalectomy is a promising alternative to open surgery although concerns exist in regard to laparoscopic treatment of pheocromocytoma. This report compares the outcome of laparoscopic and conventional (open) resection for pheocromocytoma particular in regard to intraoperative hemodynamic stability and postoperative patient comfort. METHODS: Seven patients laparoscopically treated (1997-2000) and nine patients treated by open resection (1990-1996) at the National Hospital (Rikshospitalet), Oslo. Peroperative hemodynamic stability including need of vasoactive drugs was studied. Postoperative analgesic medication, complications and hospital stay were recorded. RESULTS: No laparoscopic resections were converted to open procedure. Patients laparoscopically treated had fewer hypertensive episodes (median 1 vs. 2) and less need of vasoactive drugs peroperatively than patients conventionally operated. There was no difference in operative time between the two groups (median 110 min vs. 125 min for adrenal pheochromocytoma and 235 vs. 210 min for paraganglioma). Postoperative need of analgesic medication (1 vs. 9 patients) and hospital stay (median 3 vs. 6 days) were significantly reduced in patients laparoscopically operated compared to patients treated by the open technique. CONCLUSION: Surgery for pheochromocytoma can be performed laparoscopically with a safety comparable to open resection. However, improved hemodynamic stability peroperatively and less need of postoperative analgesics favour the laparoscopic approach. In experienced hands the laparoscopic technique is concluded to be the method of choice also for pheocromocytoma.

HLA-restricted cell-mediated cytotoxicity directed against male specific (H-Y) antigen after acute rejection of an HLA-identical sibling kidney.

A 22-year old female patient who received a kidney from her HLA-A, -B, -C and D/DR identical brother (HLA-A2, 28; B7, 14; DR1/2) acutely rejected the graft 2 1/2 weeks post transplantation. In vitro tests 1 month later, using recipient responding cells and donor stimulating/target cells, revealed: No direct cell-mediated lympholysis (CML), but strong CML against donor target cells after priming in mixed lymphocyte cultures (MLC). Testing these cytotoxic cells from the patient on the panel of non-related target cells, we found positive CML only against target cells from male donors carrying HLA-A2 and/or -B7 specificities. Both MLC and CML tests using donor responding cells and recipient stimulating and target cells were negative. These findings indicate an HLA restricted cytotoxicity against a male-specific minor histocompatibility antigen, which may be the cause of rejection in this case.

[Cancer in organ transplanted patients]. / Kreft hos organtransplanterte pasienter.

The risk of cancer in organ transplant recipients is three to five times higher than in the general population. The increased risk seems to be related to the total amount of immunosuppressive agents received. Organ transplant recipients do not have a significantly higher risk of developing the most common types of cancer, such as cancer of the breast, lungs, prostate or the uterine body. Non-melanoma skin cancers constitute well over 50% of all cancers in transplant recipients. Some forms of cancer, such as lymphomas, cancer of the cervix and Kaposi's sarcoma, are associated with viral infections. Organ transplant recipients should be regularly examined for cancer and avoid high exposure to ultraviolet light, an important aetiological risk factor for non-melanoma skin cancer. With the increasing number of new immunosuppressive drugs now being introduced, it is important to monitor their long-term side effects, including cancer.

Inhibition of blastogenic factor by alloantigen-activated human lymphocytes.

Human suppressor cells generated in mixed lymphocyte cultures (MLC) appear to inhibit both cellular proliferation and the mitogenic effects of blastogenic factor (BF). The results presented here indicate that the inhibition of BF by alloantigen-activated lymphocytes is not due to decreased lymphocyte proliferation as such, since BF normally produced by non-proliferating cultures was also suppressed. Moreover, the inhibition was not caused by direct suppression of the BF-producing lymphocytes, since incubation of BF with alloantigen-activated lymphocytes neutralized the mitogenic effects of BF. We therefore conclude that activated lymphocytes generated in human MLC directly inhibit or utilize BF. Our experiments also indicate that the activated lymphocytes do not have to proliferate to inhibit BF activity.