Lymphoid Neogenesis in Murine Cardiac Allografts Undergoing Chronic Rejection

Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd(+) HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.     

Acute Cellular Rejection with CD20-Positive Lymphoid Clusters in Kidney Transplant Patients Following Lymphocyte Depletion

Lymphoid clusters (LC) containing CD20-positive B cells in kidney allografts undergoing acute cellular rejection (ACR) have been identified in small studies as a prognostic factor for glucocorticoid resistance and graft loss. Allograft biopsies obtained during the first episode of ACR in 120 recipients were evaluated for LC, immunostained with CD20 antibody, and correlated with conventional histopathologic criteria, response to treatment and outcome. LC were found in 71 (59%) of the 120 biopsies. All contained CD20 positive B cells that accounted for 5-90% of the LC leukocyte content. The incidence of LC was highest in the patients who had no lymphoid depletion or had been treated with Thymoglobulin preconditioning (79% vs. 75%, respectively) compared to 37% in patients pretreated with Campath (p = 0.0001). Banff 1a/1b ACR were more frequent in the LC-positive than the LC-negative group (96% vs. 80%, respectively; p = 0.0051). With a posttransplant follow-up of 953 +/- 430 days, no significant differences were detected between LC-postitive and LC-negative groups in time to ACR, steroid resistance, serum creatinine and graft loss. CD20+LC did not portend glucocorticoid resistance or worse short to medium term outcomes. CD20+LC may represent a heterogenous collection in which there may be a small still to be fully defined unfavorable subgroup.     

Interleukin 4 receptor targeted cytotoxicity: genetic construction and in vivo immunosuppressive activity of a diphtheria toxin-related murine interleukin 4 fusion protein.

The interleukin 4 (IL 4) receptor is expressed on various cells of the immune system, including T and B lymphocytes, macrophages and mast cells. We have constructed a recombinant protein, DAB389-mIL 4, that is composed of the enzymatically active and membrane translocation domains of diphtheria toxin fused to murine IL 4. We demonstrate that this fusion toxin selectively inhibits protein synsthesis in eukaryotic cells which express the murine IL 4 receptor. The cytotoxic potency of this fusion toxin is shown to be directly proportional to the reported number of IL 4 receptors on the surface of target cells. Since the action of DAB389-mIL 4 can be blocked with either excess mIL 4 or antibody to mIL 4, we conclude that its entry into target cells is mediated through the mIL 4 receptor. A mutant form of DAB389-mIL 4, DA(197)B389-mIL 4, in which the fragment A-associated ADP-ribosyltransferase is inactive, is not cytotoxic to murine IL 4 receptor-bearing cells. Finally, we demonstrate that DAB389-mIL 4 administered subcutaneously to DBA/2 mice results in suppression of delayed-type hypersensitivity (DTH); whereas, the non-toxic DA(197)B389-mIL 4 fails to dampen the DTH response.     

Serum IgG and IgM levels in new and regular long-term plasmapheresis donors.

This Australian study monitored the effects of monthly plasmapheresis on donor serum IgG and IgM levels in 127 new and 124 established plasma donors who donated 1014 units over a five-month period. Of the 251 donors, 3% had reduced total serum protein (TSP) levels, 7% had low IgG levels and 12% had low IgM levels prior to donation on at least one occasion over the study period. Statistical analysis showed that the TSP, IgG and IgM levels of new donors who had donated plasma on less than 10 occasions were no more likely to fall below normal than those of old donors. However, new and old donors whose IgG or IgM levels fell below normal at any time during the study had significantly lower levels of the relevant parameter on entry to the study. Followed longitudinally, IgG and IgM levels in old and new donors tended to fall, although levels fluctuated throughout the study. Statistical analysis failed to show any correlation between TSP levels and IgG or IgM levels. These parameters did not correlate significantly with the number of previous plasmaphereses, donor weight, volume collected or history of infection. This study highlighted the need for regular, specific quantitation of IgG and IgM levels as well as TSP in regular plasmapheresis donors. The frequency of testing is yet to be determined, in view of the high materials and labour costs of such a programme.     

Comparative study of the prevalence of abnormal eating attitudes among Arab female students of both London and Cairo universities

Two matched samples of Arab female undergraduate students attending London and Cairo Universities were recruited to determine the relative prevalence of abnormal eating attitudes and the effect of exposure to Western culture upon this prevalence. A positive response was reported on the Eating Attitudes Test (EAT-40) in 22% of the students in the London group and 12% in the Cairo group, indicating that abnormal attitudes occur in this non-Western population. Six cases among the London sample fulfilled diagnostic criteria for bulimia nervosa, but no cases of either anorexia or bulimia were identified in the Cairo sample.     

Effect of the 5-lipoxygenase inhibitor ZD2138 on allergen-induced early and late asthmatic responses.

BACKGROUND--Leukotrienes are lipid mediators generated from arachidonic acid by the 5-lipoxygenase pathway which may play an important part in the pathophysiology of asthma. Previous studies have demonstrated attenuation of the allergen-induced early and late asthmatic responses by leukotriene receptor antagonists. The effect of the 5-lipoxygenase inhibitor ZD2138, a non-redox lipoxygenase inhibitor which inhibits leukotriene synthesis for 24 hours after single doses of 350 mg, on allergen-induced early and late asthmatic responses has been assessed. METHODS--Eight asthmatic subjects with baseline FEV1 > 70% were studied. On screening, all subjects developed an allergen-induced biphasic asthmatic response to grass pollen, cat dander, or house dust mite. ZD2138 (350 mg) or placebo was given on two occasions separated by two weeks in a randomised double blind fashion. Allergen inhalation challenge was performed four hours after dosing and FEV1 was measured for eight hours. The inhibitory activity of ZD2138 on the 5-lipoxygenase pathway was assessed by measurements of calcium ionophore-stimulated generation of LTB4 in whole blood ex vivo and by analysis of urinary LTE4 levels before administration of drug or placebo and at regular intervals after oral drug dosing and allergen challenge. RESULTS--ZD2138 produced no significant bronchodilatation or attenuation of the early or late asthmatic response, although there was 82% inhibition of whole blood generation of LTB4 in response to calcium ionophore stimulation and 52% reduction in urinary excretion of LTE4. CONCLUSIONS--In asthmatic subjects the 5-lipoxygenase inhibitor ZD2138 did not protect against allergen-induced asthmatic responses, despite substantial inhibition of 5-lipoxygenase.     

Fusidic acid in infections of the external eye

Summary A newly developed 1% eye preparation of the potent antistaphylococcal antibiotic fusidic acid, showed an excellent clinical effect in 206 Egyptian children with external eye infections. The 248 patients included in the study were randomized, in the ratio 5:1, to either fusidic acid or chloramphenicol 0.5% eye drops. Both preparations were given four to six times daily for one week. Bacterial conjunctivitis was diagnosed in 56% of the children. Offending eye pathogens were mainlyStaphylococcus aureus (60%),Haemophilus aegyptius (10%),Streptococcus pneumoniae (13%) andNeisseria gonorrhoeae (6%). The overall clinical success rate in children with bacterial conjunctivitis was 85% with fusidic acid, compared to 48% with chloramphenicol (p < 0.001). The better effect of fusidic acid could be ascribed to a lower frequency ofin vitro resistance (16%) in comparison to chloramphenicol (55%). Both drugs were apparently well tolerated and no side-effects were observed.

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Fusidinsäure zur Behandlung von externen Augeninfektionen

Zusammenfassung Eine neuentwickelte 1%ige ophthalmologische Präparation des gegen Staphylokokken hochwirksamen Antibiotikums Fusidinsäure erwies sich bei 206 ägyptischen Kindern mit externen Augeninfektionen als hervorragend klinisch wirksam. Die im Rahmen der Studie behandelten 248 Kinder erhielten nach Randomverfahren im Verhältnis 5:1 entweder 1%ige Fusidinsäure- oder 0.5%ige Chloramphenicol-Augentropfen. Beide Präparate wurden eine Woche lang vier-bis sechsmal täglich verabreicht. Bei 56% der Kinder wurde eine bakterielle Konjunktivitis diagnostiziert. Die häufigsten pathogenen Erreger der Augeninfektionen warenStaphylococcus aureus (60%),Haemophilus aegyptius (10%),Streptococcus pneumoniae (13%) undNeisseria gonorrhoeae (6%). Mit Fusidinsäure wurde bei 85% der Kinder mit bakterieller Konjunktivitis ein Therapieerfolg erzielt, mit Chloramphenicol in 48% der Fälle (p < 0,001). Die therapeutische Überlegenheit von Fusidinsäure ließ sich darauf zurückführen, daß dieIn vitro-Resistenz der Erreger mit 16% der Isolate in der Fusidinsäure-Gruppe geringer war als in der Chloramphenicol-Therapiegruppe mit einer Resistenzrate von 55% der Isolate. Beide Medikamente wurden offensichtlich gut vertragen, Nebenwirkungen wurden nicht beobachtet.