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Matching at the MHC class I K locus is essential for long-term engraftment of purified hematopoietic stem cells: a role for host NK cells in regulating HSC engraftment.

The events that regulate engraftment and long-term repopulating ability of hematopoietic stem cells (HSCs) after transplantation are not well defined. We report for the first time that major histocompatibility complex (MHC) class I K plays a critical role in HSC engraftment via interaction with recipient natural killer (NK) cells. Durable engraftment of purified HSCs requires MHC class I K matching between HSC donor and recipient. In the absence of MHC class I K matching, HSCs exhibit impaired long-term engraftment (P =.01). Dependence on MHC class I K matching is eliminated in B6 beige mice that lack NK cell function, as well as in wild-type mice depleted of NK cells, implicating a possible regulatory role of NK cells for HSC engraftment. The coadministration of CD8+/T-cell receptor-negative (TCR-) graft facilitating cells (FCs) matched at MHC class I K to the HSC donor overcomes the requirement for MHC class I K matching between HSCs and recipient. These data demonstrate that FCs inhibit NK cell effects on the HSCs. Notably, FCs do not suppress the cytotoxic activity of activated NK cells. Enhanced green fluorescent protein-positive (EGFP+) FCs persist for one month following allogeneic transplantation, making cold target inhibition an unlikely mechanism. Therefore, MHC class I may play a critical role in the initiating events that dictate HSC engraftment and/or NK-mediated rejection following allogeneic transplantation.

Animals↗

Insulin secretion decline unrelated to jejunal morphology or exocrine pancreatic function in children with celiac disease.

We describe a prospective 10-year study of insulin secretion and immunologic changes in a group of children with celiac disease (CD) on a gluten-free diet. Thirty CD patients aged 4-16 years and 30 matched controls were examined. They underwent i.v. glucose tolerance test during which glucose disappearance rate (K) and first phase insulin response (FPIR) were measured. Typing for HLA A, B, C, and DR antigens was performed and sera were analyzed for cytoplasmic islet cell antibodies (ICA) on several occasions. Pancreatic isoamylase (PIA) was measured to assess exocrine pancreatic function. In 4/21 CD children, FPIR and K rate were decreased. There was a significant correlation between the two parameters (p < 0.01). The incidence of HLA B8 and DR3 was higher in CD (33% and 60%, respectively) than in healthy individuals (p < 0.001). All patients were found to be ICA negative at the time of the study and at follow-up. There was no correlation between parameters of endocrine (FPIR, K) and exocrine (PIA) pancreatic function. One out of four children with reduced FPIR developed overt DM during the study. In conclusion, the decline of first phase insulin secretion documented in CD patients is unrelated to jejunal morphology or exocrine pancreatic function. This decline may be an expression of a prediabetic phase as observed in one of the subjects who finally developed IDDM. HLA B8 and DR3, which are detected in celiac patients, may indicate a possible common pathogenic mechanism between CD and IDDM.

Adolescent↗

Cytotoxic antibody complicating platelet support in acute leukemia. Response to chemotherapy.

Lymphocytotoxic or thrombocytolytic antibodies were detected in 11 of 25 thrombocytopenic patients receiving repeated platelet transfusions. Platelet survival times were reduced in these patients (half-life [T/2], 32 hours) as compared to patients without antibody (T/2, 51 hours, P less than .05). In one woman with acute myeloblastic leukemia and a potent platelet antibody, combination chemotherapy resulted in a profound decrease in circulating gamma-globulin and concurrent disappearance of the cytotoxic antibody. The survival of transfused platelets in this patient was dramatically improved, and bleeding was controlled.

Adolescent↗

Leucoagglutination and cytotoxicity of the serum of infected mice and of extracts of Trichinella spiralis larvae and the capacity of infected mouse sera to prolong skin allografts.

The sera of mice infected with the nematode Trichinella spiralis agglutinate and kill homologous lymphoid cells in vitro. The agglutinating activity is present in the sera of infected animals on the 7th day following inoculation with the parasite, rises to a maximum on the 30th day of the infection and then decreases. The leucoagglutinating titre of these sera is related neither to the level of the inoculating dose of parasites nor to the intensity of muscle infection. The agglutinating and leucotoxic activity of the sera of infected mice is probably due to the same factor(s), but target cells require sensitization before cytotoxicity becomes apparent. Skin allografts were prolonged in infected animals or in animals treated with the serum of infected animals. Saline extracts of T. spiralis larvae also have leucoagglutinating and leucotoxic activity.

Agglutination Tests↗

Burkitt's lymphoma and HL-A antigens.

Studies were carried out on the distribution of HL-A antigens in 33 patients with Burkitt's lymphoma from several tribal groups in Kenya. The frequency of distribution of the HL-A antigens was not significantly different in these patients from that in a selected control population. Difficulty was experienced in the precise identification of some HL-A antigens in Africans using a Caucasoid serum panel, in particular those associated with HL-A7 and to a lesser extent, the "W19" complex.

Adolescent↗

[Tissue typing using a Soviet automated luminescent microscope-photometer].

Automated fluorescent microscope developed by the authors permits photometry of microquantities of cellular suspensions in scanning standard 60-well plates with a flat bottom. Automated and semiautomated modes of operation are possible. Fluorescent stains and schemes of staining the examined cells that yield stable results in the lymphocytotoxic test have been selected. Comparative analysis of the efficacies of histocompatibility antigens detection by the routine and the fluorescent technique has shown a number of advantages of the fluorescent method. Specific features of fluorescent stains used for staining live cells are described.

Histocompatibility Testing↗

Toxicity and efficacy of anti-T-cell ricin toxin A chain immunotoxins in a murine model of established graft-versus-host disease induced across the major histocompatibility barrier.

Graft-versus-host disease (GVHD) was induced across the murine major histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow and splenocytes into lethally irradiated B10.BR (H-2k) murine recipients. An immunotoxin (IT) composed of a pan T-cell monoclonal antibody called anti-Ly1 (the murine homologue to human anti-CD5) was conjugated to ricin toxin A chain (anti-Ly1-RTA) and used to treat recipient mice. In vitro, IT was as active as free RTA, bound selectively, and inhibited T-cell proliferation even in the absence of potentiators. Mice administered anti-Ly1-RTA in vivo during ongoing GVHD, at a dose of 10 micrograms/d for 5 days, showed lower numbers of splenic Thy1.2+ T cells and significantly improved survival as compared with mice given phosphate-buffered saline (PBS) or irrelevant control RTA IT. Protection was transient because GVHD and weight loss occurred when injections ceased. Survival could not be enhanced by crosslinking RTA30, a low oligosaccharide-containing fraction of purified RTA. Treatment with anti-Ly1-RTA caused a significant elevation in neutrophils, and higher doses were associated with mild hepatotoxicity. In contrast, infusion of identical doses and schedules of another pan T-cell immunotoxin, anti-Thy1.2-RTA, caused a significant decrease in lymphocytes, but not neutrophils; a precipitous increase in weight; a decrease in total plasma protein (TPP); and an increase in pleural and peritoneal effusions reminiscent of vascular leak syndrome (VLS). Although the toxic effects of anti-Thy1.2-RTA were too severe to show a survival advantage in a GVHD model, histopathologic studies showed a definite anti-GVHD effect. The most significant decline in GVHD as compared with the PBS-treated controls was observed in skin, and to a lesser extent, in liver and lung. To investigate the cause of IT toxicity, anti-Thy1.2-RTA was administered intraperitoneally to lethally irradiated B10.BR (H-2k) recipients of syngeneic bone marrow. These recipients showed the same weight gain, hypoproteinuria, and VLS observed in the GVHD model. Death occurred at higher anti-Thy1.2-RTA doses (30 or 50 micrograms/daily injections administered days 8 through 12 posttransplant). Anti-Thy1.2-RTA had a negligible effect on renal function, but histologic studies showed patchy dropout of the renal tubules. Treatment resulted in pulmonary vascular congestion, but there was no pathologic evidence of liver, brain, or colon toxicity. Weight gain was enhanced by irradiation because nonirradiated normal mice did not undergo such a precipitous weight increase.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗