Christian Schmitt

Effect of isoprinosine on in vitro proliferative responses of human lymphocytes stimulated by antigen

Isoprinosine, a synthetic purine derivative, did not significantly interfere with the thymidine uptake of triggered normal lymphocytes, nor exhibit a detectable mitogenic activity. Isoprinosine was able to significantly enhance specific proliferative responses of human lymphocytes from sensitized donors to soluble antigens. Isoprinosine did not alter the early interaction of human mononuclear cells with 125I-labelled antigen, nor the expression of their membrane receptors for immunoglobulin Fc fragments. The agent could not replace the accessory rôle of adherent cells in proliferative responses to antigens. The enhancing effect of isoprinosine on antigen specific responses of T-cells was observed upon adding the compound on any one of the seven days of culture. Isoprinosine partially restored the inhibited proliferation of lymphocytes cultured in the presence of deoxyadenosine and deoxycoformycin. Data suggest that metabolic changes involving purines may account for the effect of isoprinosine on the expression of T-cell responses.

NK cells and surveillance in humans

Natural killer (NK) cells are part of the innate immune system and help to protect against infections and tumour transformation by eliminating affected cells. NK cells become activated upon target cell recognition through the integration of signals provided by both activating and inhibitory receptors. Ligands recognized by these receptors include major histocompatibility complex class I, stress-induced molecules, adhesion proteins and other molecules that are used by NK cells to identify cells to be killed. This recognition constitutes the basis of NK immunosurveillance, and its full understanding is important for therapeutic purposes, such as haploidentical bone marrow transplantation for haematological malignancies. Human NK cells are also found abundantly in the uterine decidua during early pregnancy. Besides a detrimental role in reaction to the semi-allogeneic fetus, these uterine NK cells help to create a balanced environment for the conceptus, influencing important processes such as blastocyst implantation, trophoblast invasion and spiral artery development. This review summarizes the different aspects of human NK cell biology implicated in immunosurveillance.

HACE1, a Potential Tumor Suppressor Gene on 6q21, Is Not Involved in Extranodal Natural Killer/T-Cell Lymphoma Pathophysiology

Extranodal natural killer-T-cell lymphoma (NKTCL) of nasal type is a malignant disorder of cytotoxic lymphocytes of natural killer or more rarely T cells, associated with clonal Epstein-Barr virus infection. NKTCL is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of NKTCL is little understood, some insight has been gained in the recent years, especially from genome-wide studies, which revealed a deletion on chromosome 6q21 in more than 50% of patients. Of interest, this deleted region contains four candidate tumor suppressor genes whose decreased expression has been confirmed at the mRNA level: PRDM1, ATG5, AIM1, and HACE1. Mutations and methylation in PRDM1, ATG5, and AIM1 have been reported in NKTCL cell lines. We investigated the involvement of HACE1 in NKTCL pathophysiology. Even though the hypermethylation of CpG-177 island located directly upstream of HACE1 locus led to down-regulation of HACE1 mRNA, the protein product was expressed at nearly normal levels and was functional in the NKTCL cell lines regardless of 6q21 deletion (and indeed no double deletion of 6q21 and no nonfunctional mutations have been reported). Furthermore, contrary to previous report, overexpression of HACE1 by transduction of recombinant protein did not affect proliferation or survival of NKTCL cell lines. We therefore conclude that HACE1 is not directly involved in NKTCL pathophysiology.

Serum IgE and IgG Antibodies to Tetanus Toxoid and Candidin in Immunodeficient Children with the Hyper-IgE Syndrome

Serum IgG and IgE antibodies directed against tetanus toxoid and candidin were measured using a solid-phase radioimmunoassay in seven patients with the immunodeficiency syndrome with hyper-IgE. In parallel, six normal children, three normal adults, and eight patients with or without elevated serum IgE (including atopic diseases,Candida infections, and active schistosomiasis) were studied. Serum IgG antibodies to tetanus toxoid and candidin were present in the hyper-IgE patients in concordance with their immunization history. High concentrations of IgE antibodies against both antigens were found in the immune hyper-IgE patients but not in the controls. This suggests that elevated IgE antibody responses in the hyper-IgE syndrome results from a primary defect of IgE class regulation rather than an abnormal or deficient antibody response.

Lack of evidence that HACE1 is not a tumor suppressor gene in NKTCL: to the editor-in-chief. Authors' reply.

We thank Dr. Küçük and colleagues for their comments on our published article and for raising their concerns about our conclusion that HACE1 is not a tumor suppressor gene in natural killer/T-cell lymphoma (NKTCL). The first criticism refers to the fact that we mainly studied T cell lines in which the HACE1 tumor suppressor gene in NKTCL was reported in NK-cell lymphoma. NKTCL is essentially a disease of cytotoxic cells in which the nature of T or NK cells has never been related to the differences in clinical presentation, treatment response, or prognosis, although about 80% of NKTCL cases have been reported to be of NK origin. We studied six NKTCL cell lines of which only half were of T cell origin. We also studied three NK cell lines: MECO4, YT, and SNK6. SNK6, in particular, harbors the 6q21 deletion with no difference in the T and NK cell lines concerning the lack of apoptosis induction by HACE1. The second criticism concerned the use of IL-2eactivated peripheral blood lymphocytes (PBLs) as control for protein detection. NKTCLs are not exclusively of NK origin; we were therefore careful to have a control population to reflect both Tand NK-cell content. Indeed, with high-dose IL-2 present from the beginning of the PBL culturedcirculating NK cells constitutively express a functional IL-2 receptor comprising the noncovalently associated CD25, CD122, and CD132dand after a short time of amplification (7 to 10 days), we obtained a PBLeIL-2 cell population that contained 20% to 30% NK cells. We believe that such a cell population is a relevant control for NKTCL cell lines. Third, regarding the experiments presented in Figure 5 and use of 7AAD versus Annexin V to measure apoptosis: we disagree that 7AAD measures only late apoptotic cells. The