Laisvyde Statkute

Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis

Autologous hematopoietic stem cell transplantation (HSCT) utilizing a myeloablative regimen containing total body irradiation has been performed in patients with systemic sclerosis (SSc), but with substantial toxicity. We, therefore, conducted a phase I non-myeloablative autologous HSCT study in 10 patients with SSc and poor prognostic features. PBSC were mobilized with CY and G-CSF. The PBSC graft was cryopreserved without manipulation and re-infused after the patient was treated with a non-myeloablative conditioning regimen of 200 mg/kg CY and 7.5 mg/kg rabbit antithymocyte globulin. There was a statistically significant improvement of modified Rodnan skin score whereas cardiac (ejection fraction, pulmonary arterial pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates are 90 and 70% respectively. Autologous HSCT utilizing a non-myeloablative conditioning regimen appears to result in improved skin flexibility similar to a myeloablative TBI containing regimen, but without the toxicity and risks associated with TBI.

Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m2 and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohns disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34+ cells/μl differed significantly by disease. Collected CD34+ cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34+ cell yields, respectively. Ex vivo CD34+ cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34+ cells/μl correlated positively with initial CD34+ cells/kg/apheresis and enriched product CD34+ cells/kg. Mean WBC and platelet engraftment (ANC>0.5 × 109/l and platelet count >20 × 109/l) occurred on days 9 and 11, respectively. Infused CD34+ cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34+ cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.

Hematopoietic Mixed Chimerism Derived from Allogeneic Embryonic Stem Cells Prevents Autoimmune Diabetes Mellitus in NOD Mice

Embryonic stem cell (ESC)‐derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC‐derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft‐versus‐host disease (GVHD). Herein, we demonstrate that ESC‐derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c‐kit expression, and injected either i.v. or intra‐bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end‐stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic‐specific autoantigen, but responded normally to third‐party antigens. ESC‐derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC‐derived HSC cells treating disease in an animal model.

Autologous non-myeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis.

Objective: For patients with systemic vasculitis (SV) refractory to conventional therapy, new treatment strategies aimed at aggressive induction of remission and relapse prevention are being sought. We herein report our single-centre experience in treating four patients with refractory SV employing non-myeloablative autologous haematopoietic stem cell transplantation (HSCT). Methods: Four patients with refractory SV (two with neurovascular Behcet disease, one with neurovascular Sjögren syndrome, and one with Wegener granulomatosis) were involved in an Institutional Review Board (IRB) and US Food and Drug Administration (FDA) approved phase I clinical trial of high dose chemotherapy and autologous HSCT. Peripheral blood stem cells were mobilised with cyclophosphamide (Cy) and granulocyte-colony stimulating factor (G-CSF). Conditioning regimen consisted of Cy 200 mg/kg and rabbit anti-thymocyte globulin 5.5 mg/kg intravenously (iv). Results: All four patients tolerated HSCT well without transplant related mortality or any significant toxicity. At median follow-up of 28 (range 22–36) months all patients were alive. Three patients (one with Behcet disease, one with Sjögren syndrome, and one with Wegener granulomatosis) entered a sustained remission at 6, 6 and 24 months, respectively, after transplant. They had significant decrease in disease activity and disease or treatment related damage, as measured by the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, respectively. All three patients who achieved remission discontinued immunosuppressive therapy at the time of transplant and have not required treatment since. One patient with Behcet disease and positive for human leukocyte antigen (HLA)-B51 has not improved after HSCT. Conclusion: We suggest non-myeloablative autologous HSCT is an alternative therapy for select patients with SV refractory to conventional immunosuppressive therapies.

Non-myeloablative stem cell transplantation for autoimmune diseases

Treatment of life-threatening autoimmune diseases in animal models with induced or spontaneous autoimmune diseases can be accomplished by a 2-step procedure involving elimination of self-reactive lymphocytes with an immune ablative conditioning regimen followed by infusion of autologous or allogeneic stem cells, respectively. In animal models it was shown that using such a strategy, autoimmunity could be adequately controlled. It is speculated that de-novo development of the T and B cell repertoire from uncommitted progenitor cells in the presence of the autoantigens may be the best recipe for re-induction of self-tolerance, similarly to the normal ontogeny of the immune system during the induction of self tolerance in fetal stage. For both autologous and allogeneic hematopoietic stem cell transplantation, a non-myeloablative stem cell transplantation (NST) regimen may be used for safer lymphoablation rather than myeloablation. In addition, for allogeneic hematopoietic stem cell transplantation engraftment of disease resistant donor stem cells will alter the genetic predisposition towards autoimmune disease susceptibility.

NONMYELOABLATIVE AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR REFRACTORY CIDP

Most patients with chronic inflammatory demyelinating polyneuropathy (CIDP) initially respond to corticosteroids, immunosuppressive drugs, IV immune globulin (IVIg), and plasma exchange (PE). However, more than half relapse, with some developing a recurrent or persistent clinical course resulting in severe disability and even death.1,2 Nonmyeloablative autologous hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases has demonstrated promising results, with reports of durable remissions and lower toxicity compared to myeloablative HSCT.3 Herein, we report the first patient treated in a phase I trial of autologous HSCT utilizing a nonmyeloablative regimen for refractory CIDP. ### Methods. Eligibility criteria include age 65 years or less; definite or probable CIDP according to the criteria of the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force; failure of standard therapy, i.e., incomplete response or relapse after corticosteroids, IVIg, or PE; and failure to respond to at least one second-line immunosuppressive drug (methotrexate, azathioprine, cyclosporine, tacrolimus, or mycophenolate mofetil [MMF]). CD34-enriched peripheral blood stem cells …

Non-myeloablative allogeneic hematopoietic stem cell transplantation for severe systemic sclerosis: graft-versus-autoimmunity without graft-versus-host disease?

Non-myeloablative allogeneic hematopoietic stem cell transplantation for severe systemic sclerosis: graft-versus-autoimmunity without graft-versus-host disease?

Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus patients with cardiac dysfunction: feasibility and reversibility of ventricular and valvular dysfunction with transplant-induced remission

Patients with cardiac dysfunction may be at increased risk of cardiac toxicity when undergoing hematopoietic stem cell transplantation (HSCT), which may preclude them from receiving this therapy. Cardiac dysfunction is, however, common in systemic lupus erythematosus (SLE) patients. While autologous HSCT (auto-HSCT) has been performed increasingly for SLE, its impact on cardiac function has not previously been evaluated. We, therefore, performed a retrospective analysis of SLE patients who had undergone auto-HSCT in our center to determine the prevalence of significant cardiac involvement, and the impact of transplantation on this. The records of 55 patients were reviewed, of which 13 were found to have abnormal cardiac findings on pre-transplant two-dimensional echocardiography or multi-gated acquisition scan: impaired left ventricular ejection fraction (LVEF) (n=6), pulmonary hypertension (n=5), mitral valve dysfunction (n=3) and large pericardial effusion (n=1). At a median follow-up of 24 months (8–105 months), there were no transplant-related or cardiac deaths. With transplant-induced disease remission, all patients with impaired LVEF remained stable or improved; while three with symptomatic mitral valve disease similarly improved. Elevated pulmonary pressures paralleled activity of underlying lupus. These data suggest that auto-HSCT is feasible in selected patients with lupus-related cardiac dysfunction, and with control of disease activity, may improve.

Novel TNF antagonists for the treatment of rheumatoid arthritis

Importance of the field: TNF antagonists have become an integral part of the standard of care for patients with rheumatoid arthritis (RA). Two additional TNF antagonists have recently been approved in the US for this indication, and clinicians will need to understand the data on the efficacy and safety of these agents in order to properly place them into the clinical treatment algorithm. Areas covered in this review: This review covers the published clinical trial data on the use of certolizumab and golimumab for RA. The literature search included manuscripts published through September 2009 and abstracts from major meetings (ACR and EULAR) in 2007 – 2009. What the reader will gain: This paper will review the efficacy and safety of golimumab and certolizumab in the treatment of RA at various stages of disease. Use of these agents will be described in the context of other available alternatives, including other TNF antagonists and other biologic therapies. Take home message: Certolizumab and golimumab have comparable efficacy and safety profiles compared with previously approved TNF antagonists. These two agents have several unique theoretical benefits when compared to existing agents, but the available published data do not suggest a clear clinical advantage at this time.

Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis

We have investigated the influence of different hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), Flt-3 ligand (Flt-3L) and thrombopoietin (TPO), on the course of relapsing experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Disease course and central nervous system histology were evaluated in all groups. When given after immunization but before either disease onset or during remission, Flt-3L, SCF and G-CSF exacerbated disease severity whereas TPO had no effect compared to non-cytokine-treated controls. When compared to controls, TPO did not exacerbate disease. We conclude that autoimmune disease severity may be affected by hematopoietic growth factors currently being employed in hematopoietic stem cell transplantation of patients with autoimmune disease. The mechanism of their effects remains unknown: it may be related to both T helper (Th) 1/Th2 skewing and/or homing of inflammatory cells to the disease-affected organ.