Induction of graft-versus-autoimmune (GVA) disease effect against refractory psoriasis by complete donor-type chimerism and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Abstract

Summary:A 67-year-old man with AML, who had a 21-year history of psoriasis without remission, received a reducedintensity transplantation from an HLA-identical sibling. The preparative regimen consisted of busulfan and fludarabine. Graft-versus-host-disease (GVHD) prophylaxis was cyclosporine and methotrexate. Psoriasis was completely resolved on day 18. The subsequent clinical course was uneventful until day 42, when psoriasis recurred at the same sites as before RIST. Peripheral blood examined on day 63 showed mixed chimerism with 54% recipient type. Cyclosporine was rapidly tapered off over the next 2 weeks. On day 90, 100% donor-type chimerism was confirmed. Subsequently, psoriasis improved simultaneously with the occurrence of mucositis and rash as a manifestation of GVHD. Scattered erythematous patches of psoriasis disappeared again by day 105. We initiated 0.5 mg/kg prednisolone on day 119, and resumed cyclosporine on day 133. At 7 months after RIST, he still suffers from chronic GVHD, but his psoriasis remains in remission for the first time in 21 years. The anti-psoriasis effect of the conditioning is mild and transient, while the graft-versus-autoimmunity effect, related to the induction of complete donor-type chimerism and GVHD, is more profound and persisting. A graftversus-autoimmunity effect lies in the delicate balance between alloimmunity and immunosuppressant used for GVHD prophylaxis/treatment. Bone Marrow Transplantation (2003) 32, 439-442. doi:10.1038/sj.bmt.1704146 Keywords: reduced-intensity stem cell transplantation; psoriasis; graft-versus-autoimmunity effect; graft-versushost disease Autologous stem cell transplantation (auto-SCT) has attracted attention for the treatment of severe lifethreatening autoimmune diseases, which include a stem cell disorder as a component. The background concept is that ablation of the diseased immune system followed by hematopoietic reconstitution with self-stem cells should restore normal immunity without attacking self-epitopes. Long-term remission and improvement have been observed in some cases after auto-SCT against autoimmune diseases. 1-6 Although auto-SCT has fewer toxicities and complications than allo-SCT, it is limited by the common recurrence of the primary diseases, especially in recipients of unmanipulated autografts. On the other hand, allo-SCT has been used to treat fatal disorders, both malignant and nonmalignant, as a curative approach. Theoretical graftversus-autoimmunity (GVA) effects due to the activation and reconstitution of donor T cells also support the effectiveness of allo-SCT against autoimmune diseases. 2,7 However, its significant treatment-related mortality has limited its application to life-threatening cases.Reduced-intensity stem cell transplantation (RIST), a new transplantation method with nonmyeloablative preparative regimens, has been developed to reduce regimenrelated toxicity (RRT) without spoiling the antitumor effect of allo-SCT. 8 The safety and efficacy of RIST have been demonstrated at our institution, with a 1-ye...

Allogeneic haematopoietic stem cell transplantation for severe autoimmune diseases: great expectations but controversial evidence

“…Here, along with cases in which post-alloSCT mixed chimaerism proved effective in controlling the AD, 40,41 there are others in which it was accompanied by relapse of AD. 42,43 The concept that complete remission of AD depends upon full donor chimaerism has been validated by the favourable effects of donor lymphocyte transfusions (DLI) post transplant, designed to obtain full donor chimaerism. [44][45][46] Unfortunately, there are also cases in which the AD relapsed in spite of full donor chimaerism.…”

Hematopoietic stem cell transplantation in multiple sclerosis: experimental evidence to rethink the procedures

“…At present, the patient is > 5 years out with no molecular evidence of CML (bcr/abl) or psoriasis [42]. Resolution of preexistence of a similar autoimmune disease following NST in a patient with refractory psoriasis with no underlying malignancy was also recently reported, thus confirming the existence of GVA effects in analogy to GVL and GVM [47]. Successful use of NST for the treatment of a patient with MS was recently accomplished at our center (Slavin, manuscript in preparation).…”

“…However, this therapeutic option is supported by experimental animal data in the literature of mixed chimerism [23,36,37,46]. Furthermore, the use of NST for induction of grafts versus autoimmunity (GVA) effects was already successfully pioneered in clinical practice [42,47]. We have documented the existence of GVA effects in a patient with CML with severe psoriasis accompanied by severe psoriatic arthritis resistant to conventional anti-inflammatory modalities treated with an NST regimen consisting of fludarabine, low-dose busulfan and anti-T-cell globulin (ATG), aiming to eradicate the leukemia as well as the underlying autoimmune disease.…”

Hematopoietic stem cell transplantation for pediatric autoimmune disease: where we stand and where we need to go

“…24 Further evidence of this comes from a report of psoriasis/psoriatic arthritis that relapsed post-HSCT concurrent with increasing host chimerism and then resolved with discontinuation of immune suppression and reversion to donor chimerism; 25 it is also supported by another case report of psoriasis, which had initially resolved post transplant and then relapsed but resolved concurrent with a GVHD flare. 26 In the latter case, the reinduction of immune suppression to treat the GVHD confounds the analysis of whether this is truly a graft vs autoimmunity (GVA) effect or merely a response to standard autoimmune therapies. Further evidence for the ability of unaffected donor-derived stem cells to cure autoimmune disease, or for the ability of allogeneic donor lymphocytes to eliminate host autoreactive ones, is an advantage in relapse-free survival of allogeneic vs autologous SCT in a retrospective comparison between the two in the setting of coexistent hematologic and autoimmune disease.…”