Understanding the problem here is beyond my pay grade, but if I had to guess I'd say it might be analogous to what happens with total CTLA-4 blockade:
In the case of T-cell immunity, one important layer of regulation is the interplay between enhancement and inhibition of T-cell responses by costimulatory molecules. It is thought that, in most cases, signals from the T-cell receptor (TCR) alone are insufficient to result in optimal immune responses,1 and a second, costimulatory signal is required to overcome a threshold for T cells to respond. This enhancement of TCR signals is provided primarily by CD28 on the T cells, which can be triggered by B7 expressed on the antigen-bearing cells.2-7 Once activated, T cells express a second receptor, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), that can also bind the same B7 molecules. In contrast to CD28, CTLA-4 actually inhibits T-cell responses, thereby applying the brakes to an ongoing immune response.8-13 Evidence that this receptor is, in fact, crucial to the maintenance of tolerance was demonstrated by CTLA-4 knockout mice that develop a lethal lymphoproliferative disease with infiltration of multiple organs by activated T cells.14,15 In contrast, transient blockade of CTLA-4 triggering with antibody can lead to enhancement of T-cell responses but also can induce autoimmunity that can include encephalomyelitis, colitis and diabetes in some mouse models.16-18
jco.org
These are the two references cited above:
Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985-988, 1995[Abstract]
Tivol EA, Borriello F, Schweitzer AN, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541-547, 1995 |
