SummaryActivation via the T lymphocyte cell surface molecule CD28 provides a potent amplification signal for interleukin 2 (IL2) production in several in vitro systems. The B lymphocyte activation antigen, B7/BB1, is a natural ligand for CD28. Here we investigate the role of CD28 and B7/BB1 in primary activation of CD4+ T lymphocytes stimulated with allogeneic B lymphoblastoid cell lines. A subset of peripheral CD4+ T cells that is unresponsive to crosslinking of CD3/T cell receptor (TCR) with CD3 monoclonal antibody (mAb) does proliferate in response to allogeneic B lymphoblasts . TCR binding to allogeneic major histocompatibility complex antigens was an absolute requirement for activation of these cells because mAbs to either CD3 or human histocompatibility leukocyte antigen (HLA) class II completely inhibited activation . CD28 and B7/BB1 antibodies inhibited T cell proliferation 90% and 84%, respectively. Similar results were obtained with the total CD4+ T lymphocyte population . Crosslinking of HLA DR antigens on small, resting B cells induced rapid expression of 117/11111, which peaked at 6 h and returned to baseline levels within 18 h. These data demonstrate that CD28-B7/BB1 binding provides an important early second signal for alloactivation of CD4+ T lymphocyte by B lymphoblasts.The results also suggest that T cells interacting with allogeneic resting B cells may induce B7/BB1 expression in the alloantigen-presenting cell as a consequence of interaction between the TCR and class II molecules .

IntroductionT cells respond to peptide antigen in association with MHC products on antigen-presenting cells (APCs). A number of accessory or costimulatory molecules have been identified that also contribute to T cell activation. Several of the known accessory molecules are expressed by freshly isolated dendritic cells, a distinctive leukocyte that is the most potent APC for the initiation of primary T cell responses. These include ICAM-1 (CD54), LFA-3 (CD58), and class I and II MHC products. Dendritic cells also constitutively express the accessory ligand for CD28, B7/BB1, which has not been previously identified on circulating leukocytes freshly isolated from peripheral blood. Dendritic cell expression of both B7/BB1 and ICAM-1 (CD54) increases after binding to allogeneic T cells. Individual mAbs against several of the respective accessory T cell receptors, e.g., anti-CD2, anti-CD4, anti-CD1 la, and anti-CD28, inhibit T cell proliferation in the dendritic cell-stimulated allogeneic mixed leukocyte reaction (MLR) by 40-70%. Combinations of these mAbs are synergistic in achieving near total inhibition. Other T cell-reactive mAbs, e.g., anti-CD5 and anti-CD45, are not inhibitory. Lymphokine secretion and blast transformation are similarly reduced when active accessory ligand-receptor interactions are blocked in the dendritic cell-stimulated allogeneic MLR. Dendritic cells are unusual in their comparably higher expression of accessory ligands, among which B7/BB1 can now be included. These are pertinent to the efficiency with which dendritic cells in small numbers elicit strong primary T cell proliferative and effector responses. (J. Clin. Invest. 1992.

Epstein-Barr virus (EBV) is an ubiquitous herpesvirus which is carried as a latent infection of B lymphocytes and salivary gland epithelial cells in over 90% of normal adults. Latently infected EBV-transformed B cells circulate at low frequency in the blood for the life of the host. These transformed B cells stimulate a heterogeneous and complex host cell response, ultimately leading to the development and maintenance of high frequencies of HLA-restricted T cells specific for the EBV-encoded nuclear antigens EBNA2-EBNA6 and the latency membrane proteins LMP-1 and LMP-2. Responses to latent EBV-encoded proteins are hierarchical with responses to certain epitopes predominating, dependent upon the HLA genotype of the host. Profound suppression of T-cell immunity may permit the emergence of polyclonal, oligoclonal or monoclonal EBV antigen-expressing lymphoproliferative disorders or malignant B-cell lymphomas expressing these latent EBV antigens. Adoptive transfer of small numbers of peripheral blood mononuclear cells or HLA-partially matched T cells from in vitro expanded EBV-specific T-cell lines derived from a seropositive marrow donor has induced durable regressions of bulky, widely metastatic monoclonal EBV lymphomas in a high proportion of cases. This review describes the current state of knowledge and hypothesis regarding the biology and immunology of EBV infection in the normal host, the features of donor, host and virus which contribute to the development of EBV-associated lymphoproliferative diseases and the mechanisms whereby they are controlled by adoptive transfer of immune T cells.

Three patients (one with idiopathic thrombocytopenic purpura [ITP] and two with thrombotic thrombocytopenic purpura [TTP]) were treated with rituximab (anti-CD20 chimeric antibody) at a dose of 325 mg/m 2 administered weekly after they failed standard therapies. The patient with ITP who did not respond to steroids and anti-D antibody administration achieved augmentation of her platelet counts up to 180 · 10 3 /mL after four doses of rituximab. Six months later, when her counts started to decrease, she received maintenance therapy with an additional course of 4 standard doses of antibody that resulted in consolidation of her platelet counts around 100 · 10 3 /mL. One patient with TTP and concurrent idiopathic nephropathy who was previously treated with plasmapheresis, steroids, and vincristine improved only after 4 weekly administrations of the antibody. Moreover, his nephrotic-range proteinuria resolved after he received rituximab. The other patient with chronic TTP who still relapsed after splenectomy received 5 doses of rituximab with concomitant plasmapheresis. His thrombocytopenia improved slowly, and his platelet count stabilized at 300 · 10 3 /mL. All three patients showed evidence of response to anti-CD20 antibody with improvement in clinical outcome as well as augmentation of platelet counts to normal levels. We conclude that rituximab is a useful immunomodulating adjunct in the treatment of refractory ITP and TTP. Am.