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Your Environment. Your Health.

Progress Reports: Michigan State University: Hepatotoxicant-Induced Immune Suppression through TGF-beta Release

Superfund Research Program

Hepatotoxicant-Induced Immune Suppression through TGF-beta Release

Project Leader: Norbert E. Kaminski
Grant Number: P42ES004911
Funding Period: 1995 - 2000

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Progress Reports

Year:   1999  1997  1996  1995 

Previous project research demonstrated that chemically-induced liver injury, as produced by CCl4 or acetaminophen, was correlated with the induction of TGF-1. The induction of this regulatory factor resulted in the enhanced activity of a subpopulation of helper T-cells (i.e., Th1 cells) which is responsible for facilitating cell-mediated immune responses but concurrently inhibit humoral immunity. This premise is further supported by the previous observation that Th2 derived cytokine which control humoral immune responses to T-cell dependent antigens, namely IL-4 and IL-5, are inhibited in the presence of TGF-1. Collectively, these findings suggest that liver injury may predispose the host to bacterial and parasitic infections for which resistance is primarily conferred through the production of antibodies. One of the major focuses during the past years has been to confirm by in vitro models that TGF-1, in the presence of relevant T-cell activation stimuli, does in fact lead to the modulation of IL-2 expression. For these studies primary T-cell preparations, mouse splenocytes and thymocytes were employed. Each of these leukocyte preparations has its inherent advantages and disadvantages. Mouse splenocytes, although a heterogeneous leukocyte preparation of which approximately 40% are T-cells, has the advantage that the T-cells are mature. Conversely, thymocytes although a relatively pure preparation of T-cells, has the drawback that the majority of cells are immature. Using these two sources of T-cells, two T-cell activation stimuli were employed, anti-CD3 monoclonal antibody which simulates the interaction between antigen and the T-cell antigen receptor (TCR), to activate T-cells. The second T-cell activation signal was initiated through CD28, a coreceptor on T-cells which interacts with the B7 protein expressed on antigen presenting cells. In light of this, the second activation signal utilized in the present studies was the combined treatment of anti-CD3/anti-CD28. It is notable that T-cells cannot be activated even partially by interactions solely through CD28. A number of striking trends emerged from these studies. Most notably, regardless of which of the two activation stimulus or T-cell preparation were employed, the presence of low concentrations of TGF-1 (<0.01 ng/ml) enhanced the production of IL-2 when T-cells were exposed to TGF-1 at the time of T-cell activation. Conversely, high concentrations of TGF-1 (<0.01 ng/ml) were markedly inhibitory for IL-2 expression in all of the cell preparations regardless of the activation stimulus. Equally striking was the observation that TGF-1 produced a greater enhancement of IL-2 expression when T-cells were given a complete activation signal (i.e., anti-CD3/anti-CD28) versus an incomplete activation stimulus (anti-CD3 alone). Another general trend was that mature T-cells (splenic T-cells) produced significantly greater amounts of IL-2 than did immature T-cells (thymocytes) both in the presence and absence of TGF-1. Lastly, TGF-1 was a potent inhibitor of T-cell proliferation especially at concentrations above 0.01 ng/ml. Collectively, these results confirm that TGF-1 is a potent modulator of IL-2 and correlates directly with immune alterations and changes in serum TGF-1 observed in mice after chemically-induced liver injury.

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