Immunosuppressors such as CPP, AZA, or MPM act almost indiscriminately on the immune system and therefore cause a certain degree of immune deficiency that is paid for by liability to infections. On the other hand, it makes them effective for use in various autoimmune diseases and in organ transplantation. However, if we are going to achieve a cure or at least induce remission in most patients without the high cost of morbity or mortality, more rational forms of treatment are imperative. Many years ago, we postulated that knowledge of the immunoregulatory circuits in each of the connective tissue diseases was needed for this purpose (8). We found that each disease reached autoimmunity by different pathways and thus their treatment would be different. This has resulted in opposing treatment possibilities for SLE and rheumatoid arthritis (RA). Anti-tumor necrosis factor therapies are now available for RA patients both with monoclonal antibodies (mAb) or recombinant receptor ligands. This may not be appropriate for SLE, but trials with mAb for SLE intervention at different immunoregulatory levels have now taken place and can teach us several lessons.
Intervention against the CD40-ligand is feasible in SLE patients (J Rheumatol, 2001) (5)
The activation of T cells, permitting them to stimulate other effector cells, is at least a two-step process. The first step is achieved by interaction between the T cell receptor and the antigenic peptides prepared and presented to it by cells of monocytic lineage known as antigen presenting cells (APC). The second step consists in T cell costimulation provided by signals involving receptor–ligand pairs on T cells or on APC. One of these entails interaction between the CD40 molecule on APC and its ligand (CD40L) on helper (CD4+) T cells. Also, the interaction between CD40L on T cells and CD40 on B cells provides extreme help to these, causing them to activate, proliferate, respond to cytokines, produce IgG antibodies, become resistant to apoptosis, and induce costimulation of other B cells. Patients with SLE may have increased numbers and expression of CD40L+ T cells, as well as elevated levels of soluble serum CD40L. In addition, the expression of CD40L on T cells from SLE patients may be prolonged, and this may contribute to the dysregulation. Intervention at the level of CD40 to CD40L interaction has been found beneficial in murine models of lupus.
In the study, symptomatic SLE patients received a single dose of a humanized monoclonal antibody to CD40L (IDEC-131) that has been shown to bind both avidly and specifically to CD40L on T cells and thus prevent the costimulatory signal. The single dose of IDEC-131 was escalated in cohorts of 3 to 5 patients each, from 0.05, 0.25, 1.0, 5.0, up to 15.0 mg/kg, and administered in a 2-hour IV infusion. Patients could be receiving a stable dose of prednisone, hydroxychloroquine, methotrexate, or nonsteroidal antiinflammatory drugs, but not other immunosuppressors or other biologic agents.
The surface antigen expression of CD3, CD4, CD8, and CD40L T cells and of CD19 B cells was determined by flow cytometry. The pharmacokinetics of the mAb were determined by enzyme-linked immunosorbent assay using the extracellular domain of CD40L linked to CD8 as antigen.
A total of 23 SLE patients with mild to moderate clinical manifestations were enrolled and followed for 3 months. Main adverse events were mild nausea, dizziness, and headache. There was no evidence of hepatic, renal, or hematologic toxicity nor of infections. There was also no evidence of treatment-related T or B cell depletion nor were there detectable antibodies to IDEC-131 in any patient. The pharmacokinetics of the higher dose groups were similar (half-life mean range: 298.7–319.7 hour) but the 0.25 mg/kg dose group had shorter half-life (123.0). Although the single dose did not result in any noticeably favorable clinical effect, the study did pave the ground for a phase II study of the effect of this form of treatment.
Preliminary results were presented at the 64th Annual American College of Rheumatology (ACR) meeting, Philadelphia, PA, October 2000 (9). The trial included 85 patients divided in 4 groups and treated with either saline or one of the 3 higher doses of IDEC-131. Each received 6 infusions over 16 weeks and had as primary efficacy endpoint the Safety of Estrogens in Lupus Erythematosus: National Assessment and Systemic Lupus Erythematosus Disease Activity Index score at 20 weeks. There were no differences in either efficacy nor in adverse events.
Another study was presented at the same meeting using a different anti-CD40L mAb (hu5c8) on 5 SLE patients with nephritis (10). A 2- to 8-fold decrease in IgG and IgM secreting B cells was seen, along with a 10- to 200-fold decrease in IgG and IgM anti-DNA secreting B cells that in 4 of 5 patients became undetectable. These reverted 168 days after the last treatment but remained below pretreatment levels in 2 patients. It would therefore seem that intervention at the CD40L could have profound and persistent effects on peripheral blood B cells and in particular on those that produce anti-DNA.
It would appear that intervention is feasible at the costimulatory level of immune regulation in SLE patients, but that this approach should be refined both in regard to the mAb used, as well as potential efficacy, perhaps with different patient selection.
Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus (Arthritis Rheum, 2000) (4)
Monocytes and B cells from SLE patients produce abnormally large amounts of interleukin-10 (IL-10), and serum levels of IL-10 correlate with disease activity. SCID mice injected with mononuclear cells (MNC) from SLE patients develop anti-DNA antibodies that are virtually abolished by anti-IL-10 mAb, but not by anti-IL-6 injection. Increased production of IL-10 explains most of the immunoregulatory defects found in SLE including the decreased production of, and response to, IL-2 and IL-1 with increased production of Th2 cytokines and impaired cell-mediated immune responses. A pilot study was therefore conducted in 6 steroid-dependent SLE patients who were given a 21-day course of 20 mg/day of an anti-IL-10 murine mAb (B-N10) and followed for 6 months. The treatment caused no untoward effects except for chills during mAb infusion on day 16 in one patient. It was attributed to immunization against the mAb and further treatment was discontinued.
A steady-state plasma level of 20 μg/ml of B-N10 was observed on days 9–11. On day 30, B-N10 was detectable in only 2 patients but by day 60 had disappeared in both. By monitoring the plasma concentration of IL-10 it could be determined by the ratio of B-N10 to IL-10 that the dose of mAb was sufficient to neutralize the IL-10 being produced. All patients had developed anti-mouse antibodies before day 60. The Mexican modification of the Systemic Lupus Erythematosus Disease Activity Index scores had decreased significantly in all patients by day 21 and decreased further by day 60. They remained low for 6 months. This allowed significant decreases in prednisone requirements by the first month that declined further up to the end of the study. The anti-DNA antibody levels decreased in only one patient but there were no changes in C3 or C4 levels.
The study includes information on the acute effect of anti-IL-10 administration on several immunologic abnormalities. Comparison was made between day 1 and day 10 samples as there had been no changes in prednisone dose in any of the patients by this time. There were decreases in T lymphocyte activation markers IL-2R, in a marker of general immune cell activation (sTNFR p75), and in several markers of endothelial cell activation (sICAM-1, sVCAM-1, and vWF). The spontaneous releases of sIL-2R and IL-10 also decreased significantly. In contrast, there were increases in the serum concentration of IL-1Ra, an antiinflammatory cytokine, and of IL-2 in the supernatants of PHA-stimulated MNC. All these findings indicate a prompt decrease of immune activity and partial restoration of T lymphocyte function upon administration of the anti-IL-10 mAb. Because of the appearance of human anti-mouse antibodies, repeated administration of this non-humanized mAb was not feasible. The study supports the central role of IL-10 production in the immune dysregulation of SLE and indicates a pathway of treatment that may be followed either with a humanized mAb or with drugs that abrogate IL-10 production (11).