P1792SUCCESSFUL TRANSPLANTATION OF STEM CELLS AND KIDNEY IN REFRACTORY LUPUS NEPHRITIS: REMOTE OUTCOMES

Background and Aims Lupus nephritis is a common part of systemic lupus erythematosus (SLE), severe autoimmune disease that affects multiple organ systems and associated with pure prognosis. Patients with lupus nephritis who experience persisted disease activity despite conventional immunosuppression are at high risk of early death. Re-setting of the immune system and self-tolerance by high-dose immunosuppressive therapy with autologous stem cell transplantation (ASCT) is a new approach in the treatment of refractory SLE. Remote outcomes of this method and effectiveness relapse treatment are still unclear and were the aims of this study. Method We report a sick woman 39 years old, with refractory severe lupus nephritis. Standard therapy was ineffective, SLEDAI score remains 22 so patient was underwent high dose immunosuppressive therapy with ASCT and included in European Group for Blood and Marrow Transplantation European League against Rheumatism (EBMT/EULAR) registry on 53 pts who received ASCT for SLE between 1996 and 2005. Ethical approval was obtained for this study from Cambridge University Hospital Ethics Committee. Results The ASCT induced complete clinical and serological remission (SLEDAI score was 0) for 3 years. Than relapse with nephritic syndrome and anti-dsDNA positivity occurred and caused renal failure, creatinine clearance decreased to 21. Despite therapy including prednisolone, 45 mg daily, and mycophenolate mofetil, 2000 mg daily, disease activity persisted, creatinine clearance remained decreasing and 3 years later became 15 ml/min. During 1 year patient was on regular hemodialysis, then renal transplantation performed. Now, follow up is 15 years after ASCT and 8 years after kidney transplantation. Patient received a standard post-transplant immunosuppression with prednisolone, 5 mg daily, tacrolimus, 2.5 mg daily, and azathioprine, 100 mg daily, and her conditions remains stable, she has functioning renal allograft, SLEDAI score is 2 (anti-dsDNA positivity in low titer). Conclusion We present the successful remote outcomes of first case of immunoablation and double transplantation of autologous stem cells and allogeneic kidney in severe refractory to conventional immunosuppression SLE with lupus nephritis.

Selection of matched unrelated donors moving forward: from HLA allele counting to functional matching

Matched unrelated donors (URD) are the most frequent source of stem cells for allogeneic hematopoietic cell transplantation (HCT) to date, with HCT performed mainly under conventional immunosuppression by methotrexate and cyclosporine. In this setting, every single allelic donor–recipient mismatch for HLA-A, -B, -C, -DRB1 (8/8), but not for HLA-DQB1, -DPB1, has a significant negative effect on overall survival (OS). When several 8/8 HLA-matched URD are available, donor age is the most important factor impacting OS. Moving forward from the traditional way of counting the number of donor–recipient HLA allele mismatches to biology-driven algorithms for functional matching has led to the unraveling of an association between permissive, low-risk HLA-DPB1 mismatches and improved outcome after URD HCT for malignant disease but not for nonmalignant disease. Functional HLA matching might prove to have increasing importance for URD selection in the era of new immunosuppressive regimens that have the potential to substantially reshuffle the role of HLA mismatches in URD HCT.

Apoptotic Cell–Induced, Antigen-Specific Immunoregulation to Treat Experimental Antimyeloperoxidase GN

BackgroundMyeloperoxidase (MPO)-ANCA–associated GN is a significant cause of renal failure. Manipulating autoimmunity by inducing regulatory T cells is potentially a more specific and safer therapeutic option than conventional immunosuppression.MethodsTo generate MPO-specific regulatory T cells, we used a modified protein-conjugating compound, 1-ethyl-3-(3′dimethylaminopropyl)-carbodiimide (ECDI), to couple the immunodominant MPO peptide (MPO409–428) or a control ovalbumin peptide (OVA323–339) to splenocytes and induced apoptosis in the conjugated cells. We then administered MPO- and OVA-conjugated apoptotic splenocytes (MPO-Sps and OVA-Sps, respectively) to mice and compared their effects on development and severity of anti-MPO GN. We induced autoimmunity to MPO by immunizing mice with MPO in adjuvant; to trigger GN, we used low-dose antiglomerular basement membrane globulin, which transiently recruits neutrophils that deposit MPO in glomeruli. We also compared the effects of transferring CD4+ T cells from mice treated with MPO-Sp or OVA-Sp to recipient mice with established anti-MPO autoimmunity.ResultsMPO-Sp but not OVA-Sp administration increased MPO-specific, peripherally derived CD4+Foxp3− type 1 regulatory T cells and reduced anti-MPO autoimmunity and GN. However, in mice depleted of regulatory T cells, MPO-Sp administration did not protect from anti-MPO autoimmunity or GN. Mice with established anti-MPO autoimmunity that received CD4+ T cells transferred from mice treated with MPO-Sp (but not CD4+ T cells transferred from mice treated with OVA-Sp) were protected from anti-MPO autoimmunity and GN, confirming the induction of therapeutic antigen-specific regulatory T cells.ConclusionsThese findings in a mouse model indicate that administering apoptotic splenocytes conjugated with the immunodominant MPO peptide suppresses anti-MPO GN by inducing antigen-specific tolerance.