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CD58 is the ligand for the CD2 molecule on human T cells and has been shown to provide a co-stimulatory signal for T cell activation. However, its physiological role is still unclear. We studied the effects of co-stimulation by CD58 on the production of T(h)1-type (IL-2- and IFN-gamma) or T(h)2 type (IL-4, IL-5 and IL-10) cytokines in an in vitro culture system of purified human T cells with CD58-transfected P815 cells and with anti-CD3 as the primary stimulus. Co-stimulation of T cells by CD58 potently induced IL-10 and IFN-gamma production (at the protein and at the mRNA level), and transforming growth factor-ss production (at the mRNA level), comparable to what can be found in CD80 co-stimulated T cell cultures. In contrast, we found low to absent IL-2, IL-4, IL-5, IL-13 and tumor necrosis factor-alpha production after CD58 co-stimulation, and this was not due to suppressive effects of endogenously produced IL-10. CD80 co-stimulation strongly induced all these cytokines. Intracellular staining for cytokine expression revealed the existence of a T cell subpopulation induced by CD58 co-stimulation to produce both IFN-gamma and IL-10. We furthermore found that the selective cytokine profile induced by CD58 co-stimulation is further accentuated by rIL-12 and by rIFN-alpha. Using cyclosporin A as an inhibitor of the calcineurin enzyme, we could show that production of all cytokines in this system is calcium dependent. CD58 co-stimulation thus induces a cytokine pattern corresponding to that described for T regulatory (T(r)) 1 cells and to the pattern reported to be induced by the newly identified B7 family member, B7-H1.

Interaction of CD28/CTLA-4 on T cells with B7 on antigen-presenting cells constitutes an important costimulatory signal for T cells and is responsible for cyclosporin A-resistant interleukin 2 (IL-2) gene expression and potentially also for prevention of anergy induction after T cell receptor triggering. In this paper, we demonstrate that addition of a monoclonal antibody to B7, which blocks B7-CD28/CTLA-4 interaction, and of cyclosporin A together, but not separately, to a primary mixed lymphocyte reaction of freshly isolated human T cells towards a human B cell line, induces nonresponsiveness of alloantigen-specific cytotoxic T lymphocyte precursors, whereas reactivity to a third party stimulator is intact. Nonresponsiveness could be reversed by culture in IL-2, indicating that anergy, and not clonal deletion, is responsible for this phenomenon. Our finding opens important perspectives for the development of new therapeutic strategies in transplantation.

We performed conventional cytogenetic analysis and fluorescence in situ hybridization in short-term cultures of normal and neoplastic kidney tissues. Cell populations carrying an extra chromosome 7 or an extra chromosome 10 as the only chromosome change could be identified in kidney tumors, mostly renal cell carcinomas, and in the surrounding kidney tissue, but not in nonneoplastic kidneys. To identify the type of cells displaying these aneuploidies, we performed in situ hybridization (ISH) with probes specific for the centromeric region of chromosomes 7 and 10 on frozen kidney tissue sections. Trisomy 7 and trisomy 10 were restricted to infiltrating inflammatory cells in the tumor as well as in the surrounding tissue. Trisomy 7 and trisomy 10 were also found in subpopulations of peripheral blood T cells of cancer patients and of normal individuals, as well as in the thymus of five normal fetuses (21-29 weeks), but not in noninvaded reactive lymph node sections of patients without malignancy. When lymphocytes were enriched from kidney tumors and surrounding tissue by either Ficoll/Hypaque density gradient or immunomagnetic selection with anti-CD3, anti-CD4, or anti-CD8 monoclonal antibodies, it was confirmed that they contained a high percentage of trisomy 7 and trisomy 10 cells. Further proof for T-lymphocyte origin of the trisomy 7 and trisomy 10 cells was obtained by simultaneous staining of lymphocytes isolated from tumor tissue with anti-CD3, anti-CD4, and anti-CD8 monoclonal antibodies and ISH. We conclude that trisomy 7 and trisomy 10, found in renal carcinomas and surrounding kidney tissue, characterize subpopulations of tumor-infiltrating lymphocytes. The biologic significance of this phenomenon is unknown and requires further investigation.

The interaction of CD28 with one of the B7 molecules (CD80 and CD86) on professional antigen-presenting cells (APC) is generally considered as the most important co-stimulatory signal for T cell activation. APC in a resting condition express either no or only low levels of B7 molecules. These are up-regulated as a result of interactions with activated T cells, thus suggesting that B7-CD28 interaction is not required at initiation of T cell activation. To study this issue, we blocked B7-CD28 interaction at various time points after in vitro stimulation of peripheral blood T cells with allogeneic monocytes. Epstein-Barr virus-transformed B cells or soluble antigens. We observed that T cell proliferation and IL-2 production were inhibited by B7-blocking agents (CTLA-4-Ig or anti-B7 mAb) almost to the same degree when added either at initiation of culture or 24 h later. B7-blocking agents still resulted in significant inhibition of allogeneic T cell activation when added after 48 h. Furthermore, when CTLA-4-Ig was added at the start of an allogeneic T cell stimulation, addition of anti-CD28 mAb after 24 h of culture nearly fully restored T cell proliferation to control levels. Finally, we demonstrate that delayed addition of B7-blocking agents together with cyclosporin A 1 day after the onset of culture of T cells with allogeneic B cells is highly efficient to induce energy as evaluated by lack of proliferation, cytotoxic T lymphocyte reactivity and IFN-gamma or IL-5 production upon alloantigen rechallenge. Taken together, our data can explain why B7 expression on APC is not required at the time of initial APC-T cell contact, and suggest that the effect of the CD28 signal indeed consists in prolonging IL-2 production and amplifying T cell responses, rather than in providing a critical co-stimulatory signal at the time of initial TCR triggering.

An adolescent girl with severe thrombotic thrombocytopenic purpura (TTP) remained in a critical condition after 3, weeks of combined treatment with antiplatelet drugs, plasma infusions and plasma exchange. The introduction of vincristine resulted in gradual improvement and eventual complete remission which lasted for 2 years. When she relapsed, immediate improvement was observed with the combined treatment of plasmapheresis and vincristine. She has now been in complete remission again for 10 months. It is suggested that plasmapheresis plus vincristine should be used as the initial treatment for children with TTP.

An infant is described with coloboma of the right eye, holoprosencephaly and diabetes insipidus without craniofacial malformations. The association is discussed in view of the development of the prosencephalon and its relation to the development of craniofacial structures.