Systemic lupus erythematosus (SLE, lupus) is a chronic autoimmune disease that is characterized by diffuse immune inflammation damage on connective tissue. Lupus occurs ten times more often in women compared to men [
Some former research has suggested that motivating autoreactive T cells may break the balance of the regulatory immune system so as to cause autoimmune diseases (ADs) [
Remarkably, in 2005, the attenuated autologous T cells were first tested in six SLE patients with mild lupus manifestations, and clinical improvements of patients including reduced SLEDAI scores and autoantibodies parameters, as well as relieved clinical features such as facial rash, were observed after four times of injections of inactivated CD4+ T cells [
Patients were enrolled who had a diagnosis of SLE according to the 1997 ACR classification criteria for more than half a year and had a positive antinuclear antibody. Patients were excluded for the following reasons: if they had severe SLE activity demonstrated by the SLEDAI score at screening (SLEDAI ≥ 15); if they suffered from important organ diseases including heart, kidney, lung, and nerve, such as central nervous system lupus and acute glomerulonephritis; if they had serious current or recent infection; if they were pregnant, lactating, or planning to be pregnant within the next year; or if they had previously received biological treatment.
As a result, sixteen patients (fifteen women and one man) were included. Their age ranged from 13 to 52, on average
The study obtained approval by Medical Ethics Committee of Sichuan University (JJ2014003). All patients provided written informed consent prior to vaccination. Patients who were under 18 years of age gained consent from their legal guardians.
The approaches for T cell discretion and expansion were similar to previous studies [
For understanding the changes of the antiautoreactive T cell antibodies in vivo after vaccine, the patients’ peripheral serum in different stages of vaccination was obtained, including pre-TCV and the fourth week (W4) and the eighth week of vaccination (W8), as the first antibody, to react with the inactivated sensitized T cells, which were previously prepared. The nuclei of these cells were colored blue by DAPI, while the secondary antibody was goat anti-human IgG antibody, FITC conjugate (Thermo fisher, Massachusetts) for green coloring, which would mark the reaction between the first antibody and the antigen.
All patients received the glucocorticoid (GC, 5–60 mg/d), hydroxychloroquine (HCQ, 0–0.4 g/d), and immunosuppressive drugs: methotrexate (MTX), mycophenolate mofetil (MMF), or leflunomide (LEF) in the same dosage as that used before, and the dosage was adjusted based on their prognosis.
Each patient was vaccinated by a single unit of vaccine (about 5 × 106 cells) every time, with bum intramuscular injection, and was revaccinated in the second, fourth, and the eighth week of vaccination.
All patients received supporting drugs during the treatment, including tablets of folic acid (4 mg/d), vitamin B (20 mg/d), calcium (varying with the age of every patient), and H2 receptor blocker, such as lansoprazole and omeprazole (15–30 mg/d). Furosemide and potassium chloride were provided for patients with edema.
Infrared therapy apparatus was used for patients with arthralgia or myalgia, keeping the same treatment protocol as before, varying from once a week to once a month. There are three kinds of infrared lights based on their wavelength: the near-, mid-, and far-infrared. Among them, the near-infrared (wavelength 700–1400 nm) kind functions best in penetrating tissues and warming blood vessels and thus causes muscle relaxation and telangiectasia, increasing peripheral bloodstream to relieve cardiovascular system related diseases and musculoskeletal pain; and the far-infrared kind is also believed to exert clinical effects [
Routine blood, blood biochemistry, and immune indexes tests were performed before every vaccination. Patients were allowed to leave in case of no discomfort in their sitting and peaceful state for 30 minutes after vaccination. Patients were followed up every four weeks when they were of low complementemia (LC) but every twelve weeks when their complements parameters were normal, with clinical manifestation, adverse events, urinary protein level, complements, and antibodies being observed, as well as adjusting the usage of their general drugs and supporting therapies.
The 16 patients were enrolled between February 6, 2015, and September 1, 2015, so, until the end of the year 2015, the latest follow-up weeks ranged from W14 to W40 among different patients—on average 27 weeks.
Descriptive statistics were adopted in noting the changes of clinic manifestation and antibodies; paired Student’s
During the TCV treatment and follow-up, most patients experienced a reduction in SLEDAI and an improvement in clinical features, including the constant remission of skin rash, ulcer, vasculitis, low complementemia, proteinuria, alopecia, fatigue, and Raynaud’s phenomena. In addition, no relapse was experienced. Specific cutaneous lesions: the facial rash of eight patients before TCV attenuated in W4 mostly and vanished at last, with no new generation and relapsing during treatment and follow-up, including the facial and shoulder-back herpes of P1, as well as the intractable facial rash of P14, which has relapsed again and again during the past fourteen years. However, P4 and P8 have experienced facial rash relapse in their W28 and W21, respectively; the facial rash of P4 happened after physical activity and that of P8 happened after inappropriate use of make-up, and both of them recovered soon by giving GC.
Nonspecific cutaneous lesions: P3 and P16 were vasculitis, manifested in severe ulcer of fingertips and bilateral metacarpophalangeal joints separately, and recovered gradually during vaccination. P3 has suffered from Raynaud’s phenomena in the winter for the past years but with no relapsing during the winter of this year. P14 also recovered from Raynaud’s phenomena with no relapsing during her treatment and follow-up.
Seven patients with arthralgia or myalgia recovered in W4 with no relapse during vaccination and follow-up. For the specific changes of clinical manifestations and SLEDAI scores in patients with TCV please see Table
Changes in clinical manifestations and SLEDAI scores of patients with TCV.
Patients | Before TCV | W4 | W8 | The latest follow-up week | ||||
---|---|---|---|---|---|---|---|---|
Clinical features | SLEDAI | Clinical features | SLEDAI | Clinical features | SLEDAI | Clinical features | SLEDAI | |
P1 | Facial and shoulder-back herpes, LC | 4 | Facial and shoulder-back herpes, LC | 2 | Facial rash | 0 | None | 0 |
P2 | Facial rash, alopecia, LC | 6 | Alopecia | 2 | None | 0 | None | 0 |
P3 | Arthralgia and myalgia, severe ulcer on finger tips, alopecia, LC, relapsing Raynaud’s phenomena in every winter | 12 | Alopecia, ulcer on finger tips | 10 | Alopecia | 2 | No Raynaud’s phenomena this winter | 0 |
P4 | Arthralgia, alopecia, LC | 6 | Alopecia | 2 | Alopecia, LC | 4 | None | 0 |
P5 | LC, proteinuria | 2 | LC, proteinuria | 2 | Proteinuria | 0 | None | 0 |
P6 | Arthralgia, edema, proteinuria, urinary occult blood, LC | 10 | Proteinuria, LC | 6 | Urinary occult blood, proteinuria | 8 | Proteinuria | 4 |
P7 | Facial rash, alopecia | 6 | Alopecia | 2 | None | 0 | None | 0 |
P8 | LC | 5 | — | — | LC | 2 | LC | 2 |
P9 | Alopecia, fatigue, myalgia, proteinuria, urinary occult blood, LC | 12 | Alopecia, proteinuria, LC | 8 | Alopecia, proteinuria, LC | 8 | Alopecia, proteinuria | 2 |
P10 | Facial rash, arthralgia and myalgia, LC | 5 | LC | 2 | LC | 2 | None | 0 |
P11 | Alopecia, arthralgia and myalgia, facial rash, fatigue, lips cyanosis, dyspnea, proteinuria | 10 | Alopecia, lips cyanosis, dyspnea, proteinuria | 2 | Alopecia | 2 | Alopecia | 2 |
P12 | Arthralgia, alopecia, edema, fatigue, LC, proteinuria | 9 | Alopecia, edema LC, proteinuria | 8 | Alopecia, edema, proteinuria | 6 | Proteinuria | 4 |
P13 | Facial rash, proteinuria, LC | 8 | Facial rash, proteinuria, LC | 6 | Facial rash, proteinuria | 4 | None | 0 |
P14 | Facial rash, Raynaud’s phenomena | 2 | Facial rash, Raynaud’s phenomena | 0 | Facial rash, Raynaud’s phenomena | 0 | None | 0 |
P15 | Arthralgia, alopecia, LC | 4 | Alopecia, LC | 4 | Alopecia | 2 | None | 0 |
P16 | Ulcer of skin on bilateral metacarpophalangeal joints, facial rash, dry mouth and eyes | 10 | Facial rash, ulcer on knuckle | 8 | Facial rash, ulcer on knuckle | 8 | None | 0 |
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“—” means data absence.
Among the 16 patients, P5, P6, P9, P11, P12, and P13 suffered from continual proteinuria before vaccination but have been improved since the TCV treatment, as Table
The changes in urinary protein and occult blood.
Patients | Before TCV | W4 | W8 | The latest follow-up week |
---|---|---|---|---|
P5 | 1 + 0.3 g | 1 + 0.3 g | 1 + 0.3 g | None |
P6 | 3 + 3.0 g, urinary occult blood 3+ | 2 + 1.0 g | 2 + 1.0 g, urinary occult blood 2+ | 2 + 1.0 g |
P9 | 2 + 1.0 g, urinary occult blood 3+ | 2 + 1.0 g | 2 + 1.0 g | 1 + 0.3 g |
P11 | 1 + 0.3 g | 1 + 0.3 g | None | None |
P12 | 3 + 3.0 g | 2 + 1.0 g | 2 + 1.0 g | 2 + 1.0 g |
P13 | 3 + 3.0 g | 2 + 1.0 g | 2 + 1.0 g | 1 + 0.3 g |
Twelve patients underwent low complementemia before first vaccination, but, in the fourth week, for eleven of them, the C3 and C4 level raised during the treatment or in the follow-up (W4: C3,
The changes in C3 and C4 parameters of patients.
Patients | C3 (0.9–1.8 g/L) | C4 (0.1–0.4 g/L) | ||||
---|---|---|---|---|---|---|
Before TCV | W4 | W8 | Before TCV | W4 | W8 | |
P1 | 0.73↓ | 0.68↓ | 0.98 | 0.12 | 0.11 | 0.14 |
P2 | 0.64↓ | 0.95 | 0.93 | 0.12 | 0.21 | 0.27 |
P3 | 0.65↓ | 1.3 | 1.09 | 0.05↓ | 0.25 | 0.17 |
P4 | 0.56↓ | 0.98 | 0.89↓ | 0.06↓ | 0.11 | 0.12 |
P5 | 1.00 | 0.91 | 1.01 | 0.03↓ | 0.09↓ | 0.13 |
P6 | 0.38↓ | 0.80↓ | 0.9 | 0.05↓ | 0.16 | 0.15 |
P7 | 1.08 | 1.04 | 1.24 | 0.14 | 0.18 | 0.27 |
P8 | 0.85↓ | — | 0.69↓ | 0.19 | — | 0.14 |
P9 | 0.64↓ | 0.59↓ | 0.62↓ | 0.07↓ | 0.11 | 0.12 |
P10 | 0.62↓ | 0.50↓ | 0.61↓ | 0.09↓ | 0.02↓ | 0.11 |
P11 | 1.02 | — | 1.05 | 0.16 | — | 0.19 |
P12 | 0.64↓ | 0.89↓ | 1.19 | 0.04↓ | 0.13 | 0.21 |
P13 | 0.58↓ | 0.66↓ | 0.91 | 0.07↓ | 0.09↓ | 0.11 |
P14 | 1.20 | — | 1.27 | 0.25 | — | 0.32 |
P15 | 0.58↓ | 0.84↓ | 0.79 | 0.16 | 0.19 | 0.16 |
P16 | 1.43 | — | 1.38 | 0.42↑ | — | 0.48 |
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“—” means data absence.
All the patients remained ANA positive during the study. Among them, P16’s ANA changed from 1 : 320 speckled pattern and 1 : 100 homogeneous pattern into 1 : 320 speckled pattern. The anti-ds-DNA antibodies of three patients (P4, P7, and P11) have turned negative in W8.
TCV has decreased the routine dosage of GC significantly. The mean GC before TCV was
The changes of routine GC dosage.
As the pictures in Figure
The changes in antiautoreactive T cell antibodies of periphery blood.
During the TCV treatment and follow-up period, two of the patients experienced low fever and mild gastrointestinal upset while T cells were injected but recovered within 30 minutes; the others underwent no significant side effects manifestation, such as flu-like symptom and urticaria.
SLE has been known for its damage to multiple systems and organs, relating to the accumulation of immune complex (IC) induced type III allergy generally. The overgenerated autoantibodies are believed to assist the formation of the immune complex (IC). During the pathogenesis of SLE, autoreactive T cells stimulate B cells to differentiate, proliferate, mature, and switch classes to support the production of autoantibodies [
Attenuated T cells are believed to alleviate manifestation of autoimmune diseases through clearing pathogenic autoreactive T cells [
Anti-idiotypic and antiergotypic networks are possible explanations for the mechanism of TCV. In brief, the anti-idiotypic network which consists of CD8+ and CD4+ anti-idiotypic T cells is a distinctive immune response of TCV. The CD8+ T cells deplete or suppress pathogenic T cells by inducing cytotoxicity to inhibit CD4+ effector T cells, while the CD4+ T cells produce cytokines (IL-4, IL-10) to promote regulatory immune balance. Both of the T cells require the help of APC. Besides, the reactive B cells may make a marginal contribution to the deletion or suppression of autoreactive T cells by providing anti-idiotypic antibodies. Antiergotypic T cells, one of the main composition elements of the antiergotypic network, were selectively activated as a result of TCV and secrete cytokines including IL-10 or TGF-
Furthermore, the evident improvement on C3 and C4 levels of patients was observed. Generally, complement is crucial for stopping the formation of IC [
GC has been an essential therapy for SLE because it works effectively in anti-inflammatory and antiallergic reactions, as well as assisting in improving SLE response to immunosuppressive therapy [
No apparent side effects were observed during the treatment and follow-up period, so we assumed attenuated T cell vaccination is safe in use for SLE, which accords with previous studies [
This quested clinical study aimed at exploring the effects of TCV on SLE patients. GC, immunosuppressive drugs, and HCQ are still mainstay treatments for SLE currently [
Currently, although former research of TCV has promised bright future in the treatment of ADs, implementation of TCV in SLE still faces great challenges. Not only are the mechanisms waiting to be interpreted through animal experiments, but also the proper treatment scheme, referring to vaccination cells, dosage, manner, and period in clinical practice due to the lack of relevant clinical studies, still remains unclear. Furthermore, each T cell vaccine is generated from every single patient distinctively; this can be an advantage or disadvantage, for, on one hand, it may hinge the extensive commercial manufacture, but, on the other hand, it highlights the idea of personalized medicine, which may benefit SLE patients more precisely. Besides, similar to any other new therapy, the health beneficial cost of TCV has to be carefully taken into account when referring to choosing the “best” treatment for patients: it is inevitable that TCV cost more in production compared to classical drugs; however, TCV works effectively in lowering medical cost by decreasing the GC usage [
To summarize, TCV was associated with remissions in clinical symptoms and reductions in SLEDAI and anti-ds-DNA antibodies and GC doses and increases in C3 and C4 levels, with no pathogenic side effects during treatment and follow-up, which may prove TCV functions effectively and safely in alleviating and regulating the manifestation of SLE patients.
Attenuated T cell vaccination
Systemic lupus erythematosus
Systemic lupus erythematosus disease activity index
Complement 3
Complement 4
Peripheral blood mononuclear cells
Autoimmune disease(s)
Glucocorticoid
Hydroxychloroquine
Methotrexate
Mycophenolate mofetil
Leflunomide
Low complementemia.
The authors disclose no competing interests regarding the publication of this paper.
Yu Kuang and Dapeng Wei contributed equally to this work.
The authors gratefully appreciate all the personnel of the Department of Immunology of Sichuan University and the Department of Rheumatology of Jinjiang District People’s Hospital of Chengdu City for their collaboration throughout the study. This work was supported by the National Natural Science Foundation of China (Grant J1103604).