Monoclonal Antibodies May Be Used to Treat Autoimmunity

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Monoclonal antibodies have been used successfully to treat autoimmune disease in several animal models. For example, a high percentage of (NZB X NZW) F1 mice given weekly injections of high doses of monoclonal antibody specific for the CD4 membrane molecule recovered from their autoimmune lupus-like symptoms (Figure 20-11). Similar positive results were observed in NOD mice, in which treatment with an anti-CD4 monoclonal antibody led to disappearance of the lymphocytic infiltration and diabetic symptoms.

Because anti-CD4 monoclonal antibodies block or deplete all TH cells, regardless of their specificity, they can threaten the overall immune responsiveness of the recipient. One remedy for this disadvantage is to try to block antigen-activated TH cells only, since these cells are involved in the autoimmune state. To do this, researchers have used monoclonal antibody directed against the a subunit of the high-affinity IL-2 receptor, which is expressed only by antigen-activated TH cells. Because the IL-2R a subunit is expressed at higher levels on autoimmune T cells, monoclonal antibody to the a subunit (anti-TAC) might preferentially block autoreactive T cells. This approach was tested in adult rats injected with activated MBP-specific T cells in the presence or absence of anti-TAC. All the control rats died of EAE, whereas six of the nine treated with anti-TAC had no symptoms, and the symptoms in the other three were mild.

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FIGURE 20-11

9 10 11 12 13 14 15 18 Age, months

FIGURE 20-11

9 10 11 12 13 14 15 18 Age, months

Weekly injections of anti-CD4 monoclonal antibody into (NZB X NZW) Ft mice exhibiting autoimmune lupus-like symptoms significantly increased their survival rate. [Adapted from D. Wofsy, 1988, Prog. Allergy 45:106.]

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Time after antibody injection, days

FIGURE 20-12

Injection of monoclonal antibody to the Vp 8.2 T-cell receptor into PL/J mice exhibiting EAE symptoms produced nearly complete remission of symptoms. EAE was induced by injecting mice with MBP-specific T-cell clones. EAE severity scale: 3 = total paralysis of lower limbs; 2 = partial paralysis of lower limbs; 1 = limb tail; 0 = normal (no symptoms). [Adapted from H. Acha-Orbea etal, 1989, Annu. Rev. Immunol. 7:371.1

10 20 30

Time after antibody injection, days

FIGURE 20-12

Injection of monoclonal antibody to the Vp 8.2 T-cell receptor into PL/J mice exhibiting EAE symptoms produced nearly complete remission of symptoms. EAE was induced by injecting mice with MBP-specific T-cell clones. EAE severity scale: 3 = total paralysis of lower limbs; 2 = partial paralysis of lower limbs; 1 = limb tail; 0 = normal (no symptoms). [Adapted from H. Acha-Orbea etal, 1989, Annu. Rev. Immunol. 7:371.1

The association of autoimmune disease with restricted TCR expression in a number of animal models has prompted researchers to see if blockage of the preferred receptors with monoclonal antibody might be therapeutic. Injection of PL/J mice with monoclonal antibody specific for the Vp 8.2 T-cell receptor prevented induction of EAE by MBP in adjuvant. Even more promising was the finding that the Vp 8.2 monoclonal antibody could also reverse the symptoms of autoimmunity in mice manifesting induced EAE (Figure 20-12) and that these mice manifested long-term remission. Clearly, the use of monoclonal antibodies as a treatment for human autoimmune diseases presents exciting possibilities.

Similarly, the association of various MHC alleles with autoimmunity (see Table 7-4), as well as the evidence for increased or inappropriate MHC expression in some autoimmune disease, offers the possibility that monoclonal antibodies against appropriate MHC molecules might retard development of autoimmunity. Moreover, since antigen-presenting cells express many different class II MHC molecules, it should theoretically be possible to selectively block an MHC molecule that is associated with autoimmunity while sparing the others. In one study, injecting mice with monoclonal antibodies to class II MHC molecules before injecting MBP blocked the development of EAE. If, instead, the antibody was given after the injection of MBP, development of EAE was delayed but not prevented. In nonhuman primates, monoclonal antibodies to HLA-DR and HLA-DQ have been shown to reverse EAE.

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