Joseph C. Marini

Monoclonal Anti-Gamma Interferon Antibodies Enhance Experimental Allergic Encephalomyelitis

Interferon-gamma (IFN-gamma) is a cytokine with multiple activities on a variety of cells. Under various circumstances, IFN-gamma can exhibit either pro-inflammatory or inhibitory actions. Treatment of SJL/J mice with a monoclonal antibody (Mab) to IFN-gamma during the afferent limb of the immune response to myelin protein produced an enhancement of acute experimental allergic encephalomyelitis (EAE), with increased morbidity, mortality and earlier onset of disease. Systemic administration of IFN-gamma did not improve or worsen clinical outcome, but delayed disease onset. Passive transfer of immune lymph node cells co-activated with MBP and anti-IFN-gamma Mab resulted in more sever disease than that induced by MBP stimulated cells or MBP and IFN-gamma co-stimulated cells. However, in vitro proliferation of an MBP specific T cell line was not influenced by IFN-gamma nor anti-IFN-gamma treatment. Mab to IFN-gamma inhibited suppressor function, in a non-specific assay. These in vivo and in vitro results suggest that systemic IFN-gamma serves as a physiological regulator of a suppressor mechanism in EAE. The abrogation of this regulatory mechanism by anti-IFN-gamma administration contributes to a more severe form of experimental allergic encephalomyelitis.

Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responses

Abstract Tumor necrosis factor-alpha (TNF-α) antagonist therapy has proven effective in inflammatory conditions such as rheumatoid arthritis and Crohns disease. There is substantial evidence that TNF-α also plays a role in the development of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, which along with leukemia relapse remains one of the 2 major impediments to success of the approach. Using a recently developed potent rat/mouse chimeric monoclonal antibody directed against murine TNF-α (CNTO2213), the authors investigated the effect of TNF-α blockade on GVHD mediated by either CD4 + or CD8 + donor T cells. The results indicated that the treatment had only a moderate effect on both a CD8 + T cell-mediated major histocompatibility complex-matched GVHD model involving multiple minor histocompatibility antigens and a p→F 1 acute GVHD model directed against a haplo-mismatched major histocompatibility complex barrier involving both CD4 + and CD8 + T cells. In contrast, treatment with the anti-TNF-α antibody had a highly significant effect (100% survival rate) on the CD4 + T cell-mediated component of this latter model. Importantly, anti-TNF-α antibody did not block the development of a graft-versus-leukemia effect against a murine myeloid leukemia challenge in either a syngeneic or allogeneic p→F 1 setting. This suggests that the inhibition of TNF-α during allogeneic hematopoietic cell transplantation may be able to diminish the inflammatory GVHD reaction without hindering effective graft-versus-leukemia responses.

Distribution of the blood-brain barrier in heterotopic brain transplants and its relationship to the lesions of EAE

The blood-brain barrier (BBB) is recognized as a barrier to the trafficking of molecules and cellular elements into the central nervous system (CNS). Horseradish peroxidase (HRP) exclusion is used as a measure of BBB integrity. The BBB is altered and becomes permeable during the course of experimental allergic encephalomyelitis (EAE). Heterotopic brain transplantation into the anterior eye chamber is a technique for studying genetic influences and the role of individual cell types on the development of EAE. Prior to EAE induction, HRP is excluded from the central portion of the transplant, demonstrating an intact BBB. In contrast, HRP localization is found at the periphery of the transplant, suggesting an incomplete barrier. However, EAE lesions typically occur within the more central regions of the transplant, where the BBB is intact, and not at peripherally located “leaky” areas. This suggests that endothelial cells at intact BBB sites may direct trafficking of lymphocytes (gating) into the CNS during the development of EAE, rather than the passive entry of lymphocytes into the CNS through a leaky BBB.