Immunoablative And Tolerance-inductive Therapy For Autoimmune Diseases

Study BackgroundAutoimmune diseases (AID) were disorders that are characterized by the production of antibodies which react with host tissues or immune effector cells that are autoreactive to endogenous peptides. According to statistica datas, the mortidity of AID reaches up to 5%, and the number of patients suffering AID is increasing year by year. AID is a multiple and refractory disease, and its pathogenesis is so comlplicated that it is hard to explain well just by only one theory. Because it is difficult to define the capital pathogenic element, and to obstruct the pathogenic process effectively, there is also deficiency of the specific therapies and drugs. Immunosuppression therapy and autologous hematopoietic stem cell transplantation (Auto-HSCT) are the first line therapies for various autoimmune disorders. Immunosuppression therapy can only be able to control symptoms, and when the drugs are stopped, the disease relapses. Auto-HSCT which is well tolerated and able to induce remission becomes the first choice for AID. However, relapse also occurs after transplantation. There probably are three reasons for the relapse: 1. The pathological changes exist in the stem cell level. 2. The mutative immunocytes are not cleared completely or they are introduced back to the body during auto-HSCT. 3. The mutative somatic cells remain. Here, we aim to solve the relapse problems and find the way to cure AID preferably.ObjectThe purpose of the present study is to analyze the effectivity and safty of the immunoablative and tolerance-inductive treatment, by investigating 3 patients with AID, as well as to make further analysis of the possible mechanisms of treatments and the feasibility of clinical application.MethodsWe treated three patients with AID who were resistant to routine treatment before the immunoablative and tolerance-inductive therapy.1. Clinical dataThe 3 patients had rheumatoid arthritis (RA),Acquired Hemophilia A (AH-A),systemic lupus erthematosus(SLE) respectively.1.1 The patient of RA, had a aGVHD after HLA-matched sibling bone marrow transplantation(BMT), then developed cGVHD. Two years after BMT had morning stiffness, joint pains and malformation; laboratory examination: showed erythrocyte sedimentation rate (ESR) 28mm/h, C-reactive protein (CRP) 55.66ug/ml, antinuclear antibody (ANA) positive, an inversion on CD4+/CD8+ ratio, natural killer cell (NK) decreased;1.2 The patient of AH-A, once had nephrotic syndrome (NS), healed by having hormone treatment, 3 years later, erythema and blister appeared, pathological section showed Pemphigoid, had remission after hormone treatment, 1 years later, had joint pains and skin ecchymosis,Ⅷ-factor activity was 16.3%, diagnosed as AH-A;1.3 The patient of SLE, had facial erythema, facial edema, Urine protein +-+++, Urine occult blood +-++, Ds-DNA positive, Sm positive, ANA positive, CRP negative, ESR 55mm/h,C3 0.58g/L, C4 0.13g/L, CD3 0.3g/L, CD8 0.4g/L, NK 2%, renal biopsy: lupus nephritis (Ⅳ);1.4 The total 3 patients had standard hormone therapy and immunosuppression therapy, but the symptoms persistent or drugs-dependent.2. immunoablative and tolerance-inductive treatments:The treatment protocol contained two parts: immunoablative + tolerance-inductive. Immunoablative: the similar condition therapy of HSCT (CTX / Fludarabine / ATG / Rituximab/Meprednisone), based on CTX + ATG. tolerance-inductive: CsA+MMF. The specific procedures were: RA patient, CTX 30mg/kg×2d + ATG 7mg/kg×2d + RTX 0.2, CsA 25mg bid + MMF 250mg bid; AH-A patient, CTX1Ig/m~2×2d + ATG 10mg/kg + Flu 25mg/m~2/d×5d, CsA 50mg tid + MMF 250mg tid; SLE patient, CTX 60mg/kg×2d + ATG16mg/kg + Mpl.0mg/kg×3d, CsA 3mg/kg/d + MMF 500mg bid.3. Infection prophylaxis and supportive cares: All patients were housed in high-efficiency particulate air-filtered isolation rooms. Intravenous granulocyte colony-stimulating factor (G-CSF) was administrated when WBC was < 1.0×10~9/L (at least for two days), until an absolute neutrophil count (ANC) was > 0.5×10~9/L.4. Standard of immuablative : an absolute lymphocyte count was close to zero.5. Standard of hematopoiesis reconstructive: ANC > 0.5×10~9 /L, lasted for 3 days; a platelet (PLT) > 20×10~9/L, lasted for 3 days.6. The time of follow-up: 32,42,43 months respectively.Results1. hematopoietic reconstitution: the time of agranulocytosis is short, PLT never below 20×10~9/L, and hematopoiesis recovery within 15d. The specific is as follows: RA patient WBC: D7 0.67×10~9/L, D8: 4.54×10~9/L; lymphocytes(Lym): D7 0.05×10~9/L, D8: 0.19×10~9/L. AH-A patient WBC: D9 0.06×10~9/L, D17: normal; Lym: D9 0.00×10~9/L, D17: 0.17×10~9/L, D34: 0.4×10~9/L. SLE patient WBC: D13 0.36×10~9/L, D15: normal; Lym: D13 0.08×10~9/L, D16: >1.0×10~9/L.2. Outcomings of treatment:The patient of RA and AH-A: the symptoms dribbled away, the results of lab tests became normal. The patient of SLE: the symptoms disappeared, 9 months later, autoantibody became negative, 30 months later, relapsed.3. Immune function reconstitution:The patient of AH-A, had lumoral immune function examination , 1-months, 10-months, 20-months, 25-months after the therapy, the reversed of CD4/CD8 ratio return to nomal, and the lumoral immune function recovered slowly.Conclusion 1. Immunoablative and tolerance-inductive therapy can be applicable as the treatment of AID, the observation demonstrate that this method might be more effective for RA and AH-A, and with the good short outcomings of SLE.2. As hematopoietic reconstruction needs short time and the infections can be controlled, it is a relatively safe approach for pediatric AID.3. The therapy may be more effctive for AID which is evolved by lymphocyte immunity, instead of stem cell.4. The therapy is easy,convenient and economical, and it can also avoid the shortage of auto stem dell pollution. Therefore, this approach deserves further study.