Although adenovirus is a major source of morbidity for immunocompromised individuals and a popular vector for gene therapy, little is known about the cellular immune responses it evokes in humans. Initial trials using adenovirus vectors have been disappointing, probably owing both to a preexisting immune response to Ad2 and Ad5, the most commonly used vector backbones, and to a response to the transgene. The former problem might be overcome by switching from the common type C adenoviruses, of which Ad2 and Ad5 are members, to other less common serotypes. Evidence for the feasibility of this approach has been provided by a rat model system. However, its success in humans depends on there being no immunological cross-reactivity between groups at the humoral or cellular level. Here, we examine the cross-reactivity of the cellular immune response to adenovirus in a human system, and find that human cytotoxic T lymphocytes (CTLs) prepared in vitro against an adenovirus from two of the six subgroups can lyse cells infected with adenoviruses from the other subgroups. Hence, the proposed use of adenovirus vectors from uncommon subgroups to evade memory immune response to subgroup C adenoviruses may not be successful. However, this same cross-reactivity indicates that adoptive transfer of CTLs generated in vitro against one adenovirus serotype may protect immunocompromised patients from infections by adenoviruses of all serotypes.

Adenovirus infections cause significant morbidity and mortality in immunocompromised patients, yet little is known about the immune response to adenovirus infections. We established a system for the generation of a cytotoxic immune response to adenovirus in vitro. Cytotoxic T cells (CTLs) were derived from normal donors by using peripheral blood dendritic cells as antigen-presenting cells. The CTLs were found to contain a mixture of effector cells that recognized virus peptides in the context of both class I and class II antigens. Endogenous viral gene expression was not required to sensitize cells to lysis by adenovirus-specific CTLs. CTLs raised against subgroup C adenovirus type 5 can lyse cells infected with subgroup B adenovirus type 11, indicating that viruses of different subgroups have epitopes in common. This system holds promise for defining the human immune response to adenovirus, including characterization of the viral protein(s) against which the response is generated, and the identity of the effector cells. Such studies are in progress.

Immunotherapies designed to prevent infection serve as an increasingly important adjunct to bone marrow transplantation (BMT). T cell immunotherapies are particularly useful for the control of virus infections, provided that T cell populations are free of graft-vs-host (GVH) activity. In this review, we describe positive and negative selection methods with which donor T cell populations devoid of GVH activity can be prepared for transfer to the immunodeficient BMT recipient. The support of patients with T cell immunotherapies may ultimately revolutionize BMT, elevating the procedure from a salvage to a front-line treatment strategy for otherwise fatal disorders.

The malignant cells of patients with acute lymphoblastic leukemia (ALL) rarely show phagocytic activity. In this retrospective survey, blasts from 7 of 196 patients with newly diagnosed ALL demonstrated phagocytic activity toward platelets and erythrocytes. The morphology and cytochemical staining properties of the cells were typical of ALL. Immunophenotyes were those of common ALL (CALLA+, HLA-DR+) for six patients and of pre-B-cell ALL (positive cytoplasmic immunoglobulin) for one. However, blast cells from six of the seven patients also reacted with myeloid-associated monoclonal antibodies (MCS.2 and/or SJ-D1). The wide overlap in the percentages of blasts expressing CALLA and those expressing myeloid-associated antigens suggests that some cells possessed both lymphoid- and myeloid-associated surface antigens. By a dual staining technique, two patients tested had blasts expressing antigens of both lineages. Each child achieved a complete remission after treatment with agents effective for ALL and remains in remission for 13+ to 20+ months. These morphologic and immunologic findings may define a distinct subtype of acute leukemia.