Impaired defense against vaccinia in a child with T-lymphocyte deficiency associated with inosine phosphorylase defect.

A case of progressive vaccinia associated with a profound deficiency of cellular immunity and a defect in inosine phosphorylase is described. A striking contrast was observed between humoral immunity, which showed little if any impairment, and a severe cellular defect affecting both markers and functions of T lymphocytes. The child died despite treatment with methosazone, levamisole, transfer factor, irradiated blood transfusions, and a thymus graft. An adequate serum level of antibody to vaccinia virus was obtained by transfer of specific immunoglobulins, but this failed to stop the progression of the disease. This observation suggests that host defense against vaccinia infection is mainly mediated by cellular immunity.     

Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using <Superscript>149</Superscript>Tb-rituximab

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5·10⁶ Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 µg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with ¹⁴⁹Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.     

Impaired natural killer activity in lymphohistiocytosis syndrome

In six patients with well-documented lymphohistiocytosis syndrome, natural killer activity was found to be profoundly impaired and could not be increased by incubation in vitro with interferon. This abnormality was not found in parents of the affected children. A clear correlation with the activity of the disease was observed, although a delay of a few weeks (possibly reflecting the life span of NK cells in blood) was seen in the disappearance of NK activity after the onset of the disease and its reappearance after remission. No absolute correlation was observed between NK activity and percentage of leukocytes detected by the Leu-7 monoclonal antibody. Our findings indicate that testing NK activity is useful for the diagnosis of lymphohistiocytosis syndrome and can be used as an index of activity of the disease, among other major clinical and biologic signs of this syndrome. Reversal of the NK activity defect (rather than detection of Leu-7 positive cells) appears to be a good criterion of complete remission.     

CDw149 antibodies recognize a clustered subset of CD47 molecules associated with cytoplasmic signaling molecules

One of the recently described antigens broadly expressed on human leukocytes is CDw149, which was defined at the 6th Human Leukocyte Differentiation Antigen (HLDA) Workshop by means of 2 monoclonal antibodies (mAbs). Molecular characterization of this antigen has been lacking. In the present study we demonstrate that these anti-CDw149 mAbs actually recognize a clustered subset of a well-defined membrane protein, CD47, also known as integrin-associated protein (IAP). This clustered subset is present on leukocytes but not erythrocytes. The anti-CDw149 mAbs bind with only low affinity to a monomeric (unclustered) subset of CD47 but with high avidity to the CD47 clusters. A fraction of CD47 is associated with large complexes containing cytoplasmic signaling molecules (Src family kinases and heterotrimeric G-proteins) similar to glycosphingolipid-enriched microdomains (GEMs), which may explain the previously described signaling capacity of CD47. The low-affinity anti-CD47 mAbs may be useful tools targeting specific receptor complexes involved in cell activation. Specific reactivity of low-affinity mAbs with clustered subsets of cell surface antigens may more generally explain the nature of poorly defined "activation forms" or activation neoepitopes described previously for several cell surface molecules.