vitro, this fusion protein (CTLA4-Ig) blocked the costimulatory pathway, Bcl-x production was negligible, and the cells died.

Immunotherapeutic Applications. The NZD mouse is an animal model for lupus. When the animal is treated with the solubilized CTLA4 receptor, which blocks costimulation through CD28-B7 interactions, autoantibody production is reduced and the life of the animal is prolonged. CTLA4-Ig had an ameliorative effect even when given late in the disease. In young NOD mice, on the other hand, CTLA4-Ig reduced the incidence of diabetes but not insulitis, and it had no effect in mice over 10 weeks of age. These partial effects may be related to the fact that CD28-B7 is not the only costimulatory pathway, but further research will be needed.

In tumor immunity, the APC must activate cytotoxic T-cells in order to eliminate tumor cells. Normally, this is done by stimulating T-helper cells, using both signals and producing IL-2 to encourage T-cell proliferation (as in A). In some cases, a precytotoxic T-cell can respond to antigen in the absence of costimulation, but this leads to anergy or apoptosis through the mechanisms described above (as in B). However, a number of studies have shown that when various costimulatory ligands are introduced into the tumor (e.g., B7, as in C), it is possible to enhance CD8 cytotoxicity in the absence of CD4 help, and even in the absence of costimulation by the tumor itself, so long as the peptide ligand is recognized. This strategy has worked in limited situations.

Another group has followed a slightly different track. Because CD28 turns on the costimulatory signal, but also leads to a negative feedback loop when the CTLA4 molecule is stimulated, they developed a monoclonal antibody against CTLA4 (as opposed to CTLA4-Ig, which is a soluble form of the molecule itself). By preventing the negative feedback signal, once the T-cell response has been activated naturally, this strategy results in a tremendous augmentation of T-cell cytotoxic responses that can eliminate certain tumors that wouldn’t be eliminated under other conditions.

In response to questions from the audience, Dr. Schwartz added the following:

• IL-2 drives the T-cells into S phase. However, the immune response is not the physiological effect of IL-2, but rather what IL-2 does to the biology of the cell. It’s nothing special, just cell cycling.

• Chemokines are part of a nonadaptive immune response in which their major role is to call in T-cells. Neutrophils in particular are the second line of defense, after the skin and mucosal tissue, and the earliest kind of hematopoietic cells to respond to inflammation, trying to destroy whatever organism or invader it finds. Chemokines are released both by the neutrophils and by local tissue. In a generalized sense, they too represent a kind of costimulation, and some investigators are beginning to think that the entire inflammatory process should be considered in up-regulating specific molecules to talk to T-lymphocytes.