AntiCD137 Induced Suppression of Autoantibodies

Self-reactive T cells escape from thymic deletion and become part of the normal T cell repertoire. In normal individuals these potentially autoreactive T cells are held in check by regulatory T cells and remain quiescent (Paust and Cantor, 2005). In individuals suffering from autoimmune disease these T cells escape the regulatory process, become activated and drive inflammatory processes, support autoantibody production and participate in tissue destruction. In diseases such as systemic lupus erythematosus and rheumatoid arthritis CD4 T cells drive the activation and differentiation of T-dependent autoantibody secreting B cells and their deletion or suppressed function blocks the development or progression of disease (Foell et al., 2003, 2004; Goronzy and Weyand, 1995; Mason et al., 2002; Seo et al., 2004; Sun et al, 2002; Wagner et al, 2004; Wofsy, 1988).

Based on our studies showing that anti-CD137 mAb treatment suppressed T-dependent humoral immunity, several laboratories including ours have shown that anti-CD137 mAb treatment provides protection against the initiation, or progression of established antibody-dependent autoimmune diseases (Foell et al., 2003, 2004; Seo et al., 2004; Sun et al., 2002). Our initial studies in NZB/W F1 lupus-prone mice focused on the long-term effects of short periods of anti-CD137 treatment on the development of SLE. Subsequent studies examined the effects of this treatment in CIA susceptible DBA/1 mice. In both situations mice were treated at varying points during disease progression. We began by measuring the ability of anti-CD137 treatment to prevent the development of autoantibodies and disease progression in young pre-diseased NZB/W F1 mice. To do this, we injected 8 week-old female NZB/W F1 mice with 200 |g of anti-CD137 I.P. once every third week until the mice reached 24 weeks of age, altogether, the mice received seven injections (Figure 5.7A). DBA/1 mice were immunized twice on days 0 and 21 with CII and injected with anti-CD137 on days 0, 6, and 21. Disease progression was followed for 100 days and joint inflammation destruction were measured (Foell et al., 2004). The results of both studies were quite striking in that disease progression failed to occur or was markedly delayed and diminished. NZB/W F1 mice given just three 200 |gI.P. injections ofanti-CD137 (one injection every third week), beginning at 26-32 weeks of age, ceased production of anti-dsDNA antibodies, and within 2-3 weeks of the first injection the level of serum anti-dsDNA IgG fell to near background levels (Figure 5.7B) and signs of disease progression were no longer evident. Impressively, the treated mice survived for over two years even though they eventually began to produce anti-dsDNA antibodies (Foell et al., 2003; Figure 5.7C). In another study we found that seventy percent of 41-week-old mice given a single I.P. injection of anti-CD137 mAbs responded to treatment in similar fashion and lived over two years (a normal life span for mice). Similarly, anti-CD137 mAbs suppressed established CIA in DBA/1 mice (Foell et al, 2004; Seo et al., 2004).

Finding that anti-CD137 treatment reversed established T-dependent anti-dsDNA responses in lupus prone mice was unexpected because we had previously shown that it was not possible to suppress established T-dependent humoral immune responses in normal mice. To determine whether NZB/W F1 mice differed from normal mice in this regard we immunized NZB/W F1 mice with SRBC and then left them alone until they reached an age when they normally show signs of developing autoimmune disease. By the time the mice reached 26 weeks of age they had moderate to high levels of anti-dsDNA antibodies in their serum. We injected the mice once with 200 |g of anti-CD137 mAbs and challenged them with SRBC. The mice were bled periodically and serum anti-SRBC and anti-dsDNA antibody titers were measured by ELISA. As observed previously, serum levels of anti-dsDNA antibodies dropped precipitously following injection of anti-CD137

at at a

70 n

CO 50H

3 40H

" 20H

Weeks

Ctrl. Anti-CD137

zi o

Figure 5.7. (A) Anti-CD137 mAbs induce suppression of anti-dsDNA antibodies. Lupus prone NZB/W Fl mice were injected I.P. with 200 |j.g of non-depleting rat anti-CD137 mAbs (filled triangles) or rat IgG (filled squares) once every third week between 8-24 weeks of age and serum anti-dsDNA antibody levels measured at the indicated times by ELISA. By 46 weeks of age all of the mice that received rat IgG had died (+). (B). Twenty-six week-old NZB/W Fl mice were injected with anti-CD137 mAbs (filled triangles) or rat IgG (filled squares) every third week until they reached 35 weeks of age and serum anti-dsDNA antibodies measured. By 46 weeks of age all of the mice that received rat IgG had died (+). (C). Survival of anti-CD137 treated NZB/W Fl mice. Thirty-six week-old NZB/W Fl were injected twice 3 weeks apart with 200 |ag of anti-CD137 mAbs and their survival followed.

10 15 20 25 30 35 40 45 Days Post-treatment

Figure 5.8. Anti-CD137 mAbs suppress anti-dsDNA but not anti-SRBC antibody production. Twenty-six week-old SRBC immune NZB/W F1 were challenged with SRBC and injected I.P. once with 200 |g of anti-CD137 mAbs one week later. The mice were then bled on a weekly basis and serum anti-dsDNA (filled circles) and anti-SRBC antibody (filled triangles) levels measured by ELISA.

10 15 20 25 30 35 40 45 Days Post-treatment

Figure 5.8. Anti-CD137 mAbs suppress anti-dsDNA but not anti-SRBC antibody production. Twenty-six week-old SRBC immune NZB/W F1 were challenged with SRBC and injected I.P. once with 200 |g of anti-CD137 mAbs one week later. The mice were then bled on a weekly basis and serum anti-dsDNA (filled circles) and anti-SRBC antibody (filled triangles) levels measured by ELISA.

mAbs. Nevertheless, anti-SRBC responses remained elevated (Foell et al., 2003; Figure 5.8). The basis for this disparity is not yet clear. However, it has been shown that virus specific CD8 T cells in mice chronically infected with LCMV undergo clonal exhaustion due to constant stimulation. In this respect autoimmune mice bear a similarity to chronically infected mice in that their autoreactive T cells are constantly in a state of activation, and they too probably die through exhaustion. Therefore, disease progression can be viewed as a continuous cycle of dying exhausted autoreactive cells and an influx of newly minted naive autoreactive T and B cells lymphocytes. In such an environment anti-CD137 mAbs have no effect on existing activated autoreactive T cells, but they could suppress antigen priming of naive autoreactive T cells in the same way they suppress anti-SRBC responses. However, this is just a hypothesis and at present there is no evidence to support this notion. Furthermore, other factors must come into play in suppressing autoimmunity in NZB/W F1 mice because anti-CD137 mAbs do not suppress or reverse autoimmune diabetes, a CD4 T cell-dependent, B-cell independent disease. Perhaps the difference lies is the lifespan of autoantibody producing B cells and not autoreactive CD4 T cells. In a variation of the preceding scenario, autoreactive CD4 T cells are held in check following anti-CD137 treatment by DC induced CD4 regulatory T cells and no longer retain the capacity to provide help to B cells.

Robert S. Mittler, Liguo Niu, Becker Hewes, and Juergen Foell b

Osteoarthritis

Osteoarthritis

Thank you for deciding to learn more about the disorder, Osteoarthritis. Inside these pages, you will learn what it is, who is most at risk for developing it, what causes it, and some treatment plans to help those that do have it feel better. While there is no definitive “cure” for Osteoarthritis, there are ways in which individuals can improve their quality of life and change the discomfort level to one that can be tolerated on a daily basis.

Get My Free Ebook


Post a comment