scholarly journals THE FREQUENCY OF ANTIGEN-SENSITIVE CELLS IN TISSUE TRANSPLANTATION

1969 ◽  
Vol 129 (3) ◽  
pp. 459-467 ◽  
Author(s):  
Norman W. Nisbet ◽  
Morten Simonsen ◽  
Marek Zaleski

Graft-vs.-host (GVH) reactions were performed in chicken embryos by intravenous injection of adult chicken blood dilutions, and the result was scored by weighing the spleens as well as by karyological identification of host and donor metaphases. From the frequency of detectable signs of GVH reaction when low doses of donor cells were injected into hosts containing one foreign allele of the B locus it is concluded that 1–2% must be a minimum estimate for the frequency of antigen-sensitive cells of a given specificity in this system. It is not found possible to reconcile the findings with the strictest form of clonal selection which postulates a single receptor specificity per clone of antigen-sensitive cells.

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1530-1538 ◽  
Author(s):  
Shannon J. Opiela ◽  
Robert B. Levy ◽  
Becky Adkins

AbstractEarly life exposure to noninherited maternal antigens (NIMAs) may occur via transplacental transfer and/or breast milk. There are indications that early life exposure to NIMAs may lead to lifelong tolerance. However, there is mounting evidence that exposure to NIMAs may also lead to immunologic priming. Understanding how these different responses arise could be critical in transplantation with donor cells expressing NIMAs. We recently reported that murine neonates that received a transplant of low doses of NIMA-like alloantigens develop vigorous memory cytotoxic responses, as assessed by in vitro assays. Here, we demonstrate that robust allospecific cytotoxicity is also manifest in vivo. Importantly, at low doses, NIMA-expressing cells induced the development of in vivo cytotoxicity during the neonatal period. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses that exceeded the responses of adults. Overall, we conclude that exposure to low doses of NIMA-like alloantigens induces robust in vivo cytotoxic and Th1/Th2 responses in neonates. These findings suggest that early exposure to low levels of NIMA may lead to long-term immunologic priming of all arms of T-cell adaptive immunity, rather than tolerance.


1966 ◽  
Vol 44 (6) ◽  
pp. 981-1019 ◽  
Author(s):  
E. E. Daniel

The actions of drugs on the antrum and duodenum of the dog were analyzed by the use primarily of intra-arterial injections into the gastroepiploic artery while the electrical and contractile activity of these regions was recorded. Histamine (0.1 to 5 μg) usually caused excitation of second potentials (antrum) or fast spikes (duodenum), and contractions (both) and other effects similar to those produced by acetylcholine, though usually delayed in onset and more prolonged. Its effects were diminished or prevented by atropine, nicotine, and hexamethonium as well as by antihistaminics such as antazoline, cyproheptadine, and phenoxybenzamine. In the duodenum, histamine excitation was usually preceded by inhibition, and most antihistaminics also depressed responses to serotonin (5-HT), acetylcholine, or both. Low doses of serotonin (0.1 to 1 μg) most frequently caused excitation of the antrum and duodenum similar to that evoked by acetylcholine. This response was sometimes prolonged. These effects in the antrum were diminished or prevented by atropine, nicotine, methysergide, and bromolysergic acid (BOL), and less effectively antagonized by hexamethonium, morphine, and pronethalol. Phenoxybenzamine did not prevent excitation of the antrum by low doses of 5-HT, but tachyphylaxis following high doses of 5-HT (5 to 100 μg) or of phenyldiguanide (25 to 500 μg) did prevent such responses. Several of these agents also inhibited excitation of the duodenum induced by 5-HT and cross tachyphylaxis between 5-HT and phenyldiguanide was also observed. It was suggested that low doses of 5-HT, like phenyldiguanide, acted at a preganglionic site in the antrum and duodenum different from that at which histamine acts, presumably the non-medullated mucosal mechanoreceptors, and ultimately caused release of acetylcholine from postganglionic fibers. Phenyldiguanide in small doses (2 to 25 μg) acted like 5-HT to excite the antrum and duodenum. Analysis of its action with antagonists yielded results similar to those with 5-HT, and the occurrence of cross tachyphylaxis with 5-HT suggested a common site of action. Morphine (10 to 1000 μg) usually inhibited electrical and contractile activity in the antrum and stimulated these activities in the duodenum. The same results were obtained with intravenous injection (0.1 to 0.35 mg/kg). It. diminished responses to histamine, 5-HT, phenyldiguanide, and to a lesser extent, acetylcholine.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5056-5056
Author(s):  
Vanessa Kohl ◽  
Susanne Brendel ◽  
Johanna Flach ◽  
Helga Kleiner ◽  
Christel Weiss ◽  
...  

Malignant hematopoietic cells of myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemias (CMML) and acute myeloid leukemias (AML) may be particularly vulnerable to inhibition of poly(ADP ribose) polymerase 1/2 (PARP1/2) and apurinic/apyrimidinic endonuclease 1 (APE1). PARP1/2 and APE1 are critical enzymes involved in single-strand break repair and base excision repair, respectively. Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, as single-agents, combined with decitabine and combined with each other in CD34+ MDS/CMML cells and in CD34+ or CD34- AML cells in comparison to healthy CD34+ donor cells. The surviving fraction of CD34+ MDS/CMML cells (n = 8; 4 MDS and 4 CMML), CD34+ or CD34- AML cells (n = 18) and healthy CD34+ donor cells (n = 8) was analyzed using the CellTiter-Glo luminescent cell viability assay (Promega, Southampton, UK). Cell proliferation of untreated MDS/CMML and AML cells was determined by trypan blue exclusion assay (Merck, Darmstadt, Germany). PARP1/APE1 mRNA expression was evaluated using validated primer sets for PARP1 (Hs_PARP1_1_SG QuantiTect Primer Assay, NM_001618) and APE1 (Hs_APEX1_1_SG QuantiTect Primer Assay, ENST00000216714) (Qiagen, Hilden, Germany). Immunofluorescence microscopy of γH2AX foci was performed using a JBW301-derived mouse monoclonal anti-γH2AX antibody (Merck). Talazoparib and APE1 inhibitor III demonstrated critical anti-leukemic efficacy as single-agents in about 19-25% of MDS/CMML/AML cell samples (Figure 1A and B). Low doses of talazoparib and APE1 inhibitor III further increased the cytotoxic efficacy of decitabine in about 78-86% of MDS/CMML/AML cell samples. Moreover, low doses of APE1 inhibitor III increased the cytotoxic efficacy of talazoparib in about 68% of MDS/CMML/AML cell samples. In summary, talazoparib and APE1 inhibitor III demonstrated substantial anti-leukemic efficacy as single-agents, in combination with decitabine and combined with each other. Hence, our findings support further investigation of these agents in sophisticated clinical trials. Figure 1 Cytotoxic efficacy of talazoparib and APE1 inhibitor III in healthy CD34+ donor cells, in CD34+ myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) cells and in CD34+ or CD34- acute myeloid leukemia (AML) cells after 3 days of treatment. (A) The mean IC50 of talazoparib was significantly lower (*p = 0.016) in 1 MDS (MDS#2), 1 CMML (CMML#2) and 3 AML cell samples (AML#1, AML#2, AML#3) as compared to 8 healthy donor cell samples. (B) The mean IC50 of APE1 inhibitor III was substantially lower (p = 0.059) in 1 MDS (MDS#2) and 5 AML cell samples (AML#1, AML#2, AML#3, AML#6, AML#12) as compared to 8 healthy donor cell samples. Figure 1 Disclosures Fabarius: Novartis: Research Funding.


1970 ◽  
Vol 24 (03/04) ◽  
pp. 577-586 ◽  
Author(s):  
S Renaud ◽  
F Lecompte

SummaryPhenylbutazone, oxyphenbutazone, and sulfinpyrazone were equally effective at the dosage of 100 mg/kg (per os) in inhibiting thrombin- and ADP-induced platelet aggregation in hyperlipemic rats, and in preventing the development of thrombosis initiated by the intravenous injection of an endotoxin. Despite a slight anticoagulant effect of these substances, their antithrombotic activity appears to be due mostly to inhibition of platelet aggregation.Thrombosis in hyperlipemic rats could also be prevented by a dicoumarol derivative, acenocoumarin, which only inhibits coagulation. Therefore, both platelet aggregation and fibrin formation appear to be essential for the occurrence of large thrombi under these conditions. Nevertheless, although acenocoumarin has no direct effect on platelet aggregation, it could indirectly affect this phenomenon by blocking the formation of thrombin, which is suspected of being the agent responsible for initiating thrombosis in hyperlipemic rats.Low doses of phenylbutazone and acenocoumarin, in condition, which when given alone were ineffective in inhibiting thrombosis, could decrease the severity of thrombosis by 33%. The substance GP45840, when added in vitro to platelet-rich plasma as well as given per os to hyperlipemic rats, was no more effective than sulfinpyrazone in inhibiting platelet aggregation. Nevertheless, this substance was significantly more efficient in reducing thrombosis than was sulfinpyrazone, apparently through some additional anticoagulant activity. The results of these experiments suggest that it could be beneficial to affect both coagulation and platelet aggregation in order to satisfactorily prevent thrombosis.


1989 ◽  
Vol 30 (2) ◽  
pp. 176-184 ◽  
Author(s):  
SENTARO TAKAHASHI ◽  
YOICHI OGHISO ◽  
HIROSHI SATO ◽  
YOSHIHISA KUBOTA

Development ◽  
1959 ◽  
Vol 7 (3) ◽  
pp. 394-408
Author(s):  
P. I. Terasaki

The injection or transplantation of certain adult chicken cells into chicken embryos is known to cause a gross enlargement of the spleen and may often have fatal consequences. The enlargement produced by transplantation of adult spleen cells on to the chorioallantois has been studied by Danchakoff (1916) and by Ebert (1951, 1954). The same effect is produced by the intravenous injection of circulating white blood-cells from adult chickens (Simonsen, 1957; Terasaki, Cannon, & Longmire, 1959). The evidence of Billingham & Brent (1957, 1959), who have studied a similar phenomenon (‘runt disease’) in mice, and of Cock & Simonsen (1958) in chicks, indicates that these effects are due to the grafted adult cells reacting immunologically against the antigens of the helpless host. This type of reaction has been called the ‘graft-versus-host’ or graft against host reaction.


1986 ◽  
Vol 250 (2) ◽  
pp. R260-R266 ◽  
Author(s):  
R. Isaacks ◽  
P. Goldman ◽  
C. Kim

The O2 affinity (P50) of erythrocyte suspensions from 18-day chick embryos, from 2-, 5-, 8-, and 14-day chicks, and from mature chickens decreased with increasing concentrations of either CO2 or H+, particularly at a pH near 7.4 and at 37 degrees C. A greater effect on delta P50's was observed from increasing H+ concentration from pH 8.0 to 6.8 in cell suspensions from 18-day embryos (28.8 Torr at 0% CO2) and adult chickens (55.1 Torr at 0% CO2) than from increases in CO2 concentration at any given pH. The Bohr effect (delta log P50/delta pH) in the absence of CO2 was -0.508 and -0.479 for cell suspensions from 18-day chick embryos and adult birds, respectively. The specific effect of CO2 on the Bohr effect, regardless of the CO2 concentration, indicates that the delta P50/0.1 pH is approximately 1.35 and 2.45 Torr for the embryo and adult chicken blood. These results indicate that increasing H+ and CO2 concentrations markedly affect the P50 of chicken blood and that even subtle changes in either could play a significant role physiologically in regulating blood P50 in birds.


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