Background

[PubMed]

A characteristic feature of rheumatoid arthritis (RA) is progressive inflammation and proliferation of the synovium in the joints, but the disease may also have extra-articular manifestations (1, 2). The inflammatory response observed during RA is believed to be caused by the presence of CD4⁺ and CD8⁺ T lymphocytes in the RA-inflamed tissue, which indicates that these cells may play an important role in the pathogenesis of this disease (3). Although radiography, scintigraphy, ultrasonography, and magnetic resonance imaging with examination both before and after contrast administration are used for detecting early arthritis, none of these imaging procedures can adequately measure the state of or detect the early signs of arthritis in the tissue (4). The use of radiopharmaceuticals to detect RA has also been explored, but these bone-seeking agents accumulate nonspecifically in the arthritic joint, depicting bone metabolism rather than inflammation of the synovium (5, 6).

Because T cells are known to accumulate in the inflamed tissue during RA, the possible use of monoclonal antibodies (mAb) directed against membrane-surface molecules on T cells to detect, evaluate, and monitor the disease has been explored (7-10). Among these mAbs, the anti-CD3 antibody is directed against the CD3 antigen present on the T cells and is widely used as an immunosuppressive drug in organ transplant patients (11). This mAb is approved by the United States Food and Drug Administration for the reversal of acute renal, cardiac, or hepatic allograft rejections and is in clinical trials for the treatment of a variety of conditions involving T cells; it is available commercially. Investigators have evaluated the use of a metastable technetium (^99mTc)-labeled anti-CD3 mAb ([^99mTc]anti-CD3 mAb or [^99mTc]OKT3) for the detection of acute renal rejection in transplant patients and also for monitoring RA synovitis (7, 9, 10).

Synthesis

[PubMed]

The source of OKT3 used for the imaging work was not mentioned in the publication (9, 10). The labeling of OKT3 was described by Martins et al. (10). Briefly, the mAb was incubated with 2-mercaptoethanol for 10 min along with an exogenous chelator; the nature of the chelator was not described. Stannous chloride was added to the mAb solution, and the mixture was incubated for another 10 min. Subsequently, ^99mTc as sodium pertechnetate was added to the mixture and incubated for 20 min (incubation temperature was not provided). After the labeling reaction, the mAb was filtered through a 0.45-micron filter to remove any colloidal form of [^99mTc]OKT3. The investigators claimed that >90% of the mAb was labeled with ^99mTc (10). The stability and specific activity of the labeled mAb were not provided (10).

Marcus et al described a different method for the generation of [^99mTc]OKT3 (7). The commercial antibody was first incubated with ascorbic acid for the reduction of one or two disulphide bonds in the mAb. The conditions (time and temperature) for this incubation were not provided. The reaction mixture was then mixed with sodium pertechnetate previously reduced with sodium hydrosulphite and incubated for 30 min. Unbound ^99mTc was separated from the labeled mAb by centrifugation in a Centricon 30 microconcentrator. The radiochemical yield of the reaction was >95%, and the colloid formation was consistently <5% as determined by thin-paper chromatography and high-performance liquid chromatography on a Water’s protein pak SW 300 column. The stability and specific activity of the labeled product were not provided (7).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No references are currently available.

Animal Studies

Human Studies

[PubMed]

The use of [^99mTc]OKT3 scintigraphy to diagnose acute rejection in renal transplants was evaluated by Martins et al. (10). Among the 22 renal transplant patients in this study, an increased kidney uptake of [^99mTc]OKT3 was observed with time in 3 patients experiencing allograft rejection. A histopathological examination of the kidneys in these 3 patients confirmed the observations made with [^99mTc]OKT3 scintigraphy. The investigators reported that a larger number of kidney transplant patients were being monitored with this technique to confirm the use of [^99mTc]OKT3 to detect kidney allograft rejection.

In another study, [^99mTc]OKT3 was given intravenously to seven RA and two psoriatic arthritis patients to evaluate the use of this labeled mAb for the identification of an inflamed synovium (7). Specific regional imaging and anterior and posterior whole-body scans were performed on the patients 20 min after administration of the labeled mAb. Based on criteria for the classification of RA specified by the American College of Rheumatology, patients with asymptomatic and joints with mild pain or minimal tenderness showed normal uptake of the label. Patients who described moderate to severe pain in their joints showed moderate to marked increases in radioactivity uptake. With these results the investigators concluded that [^99mTc]OKT3 could possibly be used to measure the effectiveness of a treatment for RA and other conditions that result in an inflamed synovium (7).

Martins et al. investigated the use of [^99mTc]OKT3 to monitor RA in 38 patients (9). Planar anterior images of the patients' wrists, metacarpophalangeal and interphalangeal joints, elbows, shoulders, and knees were obtained 1 h and 3 h after administration of [^99mTc]OKT3. A significant correlation (P < 0.05) between the accumulation of [^99mTc]OKT3 and swollen or tender joints and the visual analog scale was reported. The investigators observed no correlation between the accumulation of radioactivity and the patients' age, gender, duration of disease, and erythrocyte sedimentation rate. From these results the investigators concluded that [^99mTc]OKT3 scintigraphy was a reliable and objective method to detect synovial activity, and this technique could possibly be used to observe disease prognosis.

Supplemental Information

[Disclaimers]

NIH Support

Some of the studies presented in this chapter were funded by NIH grant (MLT)CA-51960.

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