The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery

Patriarca, Francesca; Skert, Cristina; Sperotto, Alessandra; Zaja, Francesco; Falleti, Edmondo; Mestroni, Rosalba; Kikic, F.; Calistri, Elisabetta; Filì, Carla; Geromin, Antonella; Cerno, Michela; Fanin, Renato

doi:10.1016/j.exphem.2005.12.011

Cited by 134 publications

(95 citation statements)

References 30 publications

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“…To investigate whether the production of auto-antibod- ies was associated with symptoms of chronic GVHD as reported, 16,17 serum before and after rituximab treatment of patients and No-GVHD controls was tested for a panel of antibodies correlated with Systemic Sclerosis (SSc) in terms of quality (type) and quantity. Several auto-antibodies were found in serum of both responders and nonresponders, as well as in serum of No-GVHD controls.…”

Section: Resultsmentioning

confidence: 99%

The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Dorp¹,

Resemann²,

Boome³

et al. 2011

Haematologica

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1380haematologica | 2011; 96(9) IntroductionGraft-versus-host-disease (GVHD) is the most common and life-threatening complication after allogeneic stem cell transplantation (allo-SCT).1,2 B-cell depletion with rituximab (RTX) has been successful in steroid-refractory chronic GVHD, showing response rates of 43-80%. [3][4][5][6][7][8] However, the nature of B-cell contribution, as well as to what extent B-cell depletion can restore physiological conditions, has so far not been clarified. Hypotheses obtained from mouse models of chronic GVHD and retrospective analysis of patient materials have been conflicting. For example, a correlation was found between high levels of B-cell activating factor (BAFF) in a retrospective analysis of 45 patients with active chronic GVHD.9 However, no significant correlation could be found between the levels of BAFF and RTX-responsiveness in the most recently published prospective phase II study of 37 patients. 10 In active chronic GVHD prior to response to immunosuppressants, expansion of activated CD27 + B cells has been observed. 9 Another retrospective study of 35 patients suffering from active chronic GVHD, in which treatment included prednisone and calcineurin inhibitors, showed significantly lower numbers of memory B cells (CD27 + ). 11 To our knowledge, no prospective comparisons have been made between immune subsets before and after B-cell depletion therapy of steroid-refractory chronic GVHD, so details on reestablishment of normal B-cell pools after RTX treatment, as well as changes in immune-pathology of the skin, still have to be clarified. Consequently, the aim of this study was to demonstrate effectiveness of B-cell depletion therapy in steroid-refractory chronic GVHD and to identify potentially involved cell subsets by a comprehensive immunological analysis in a prospective clinical trial. Design and Methods Patients and patient materialIn the course of a prospective study (Eudra-CT 2008-004125-42), a cohort of 20 chronic GVHD patients who received allo-SCT due to various hematologic malignancies was treated with 4 weekly doses of 375 mg/m 2 RTX (F. Hoffmann-La Roche Ltd., Basel, Switzerland). All patients had chronic GVHD with at least skin symptoms. Inclusion criteria were age over 18 years, life-expectancy of more than six months, and a World Health Organization (WHO)The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versushost disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression...

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Section: Resultsmentioning

confidence: 99%

The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Dorp¹,

Resemann²,

Boome³

et al. 2011

Haematologica

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“…There are numerous examples of autoantibody formation in patients with cGVHD, though their role in its pathogenesis has not been elucidated. 48 Of particular note is a study in which antibodies to platelet derived growth factor were observed in patients with cGVHD but not in those without it. 49 These antibodies had the capacity to induce both tyrosine phosphorylation of PDGF receptor and type I collagen gene expression by fibroblasts.…”

Section: -19mentioning

confidence: 99%

Immune modulation and chronic graft-versus-host disease

Soiffer

2008

Bone Marrow Transplant

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“…Anti-nuclear, -mitochondrial, -parietal, -smooth muscle and -parotid autoantibodies are present in some persons with cGVHD. 35,36 Also, persons with autoantibodies have more cGVHDassociated symptoms than persons without autoantibodies. 35 Autoantibodies against platelet-derived growth factor receptor may have a role in cGVHD.…”

Section: Pathophysiologymentioning

confidence: 99%

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

Linhares

Pavletić

Gale

2012

Bone Marrow Transplant

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Chronic GVHD (cGVHD) is an important problem after allotransplants. Some risk factors for cGVHD are similar to those of acute GVHD (aGVHD) but others are distinct indicating sometimes overlapping but unique pathogeneses. Precise incidence and prevalence data of cGVHD are lacking because of diverse diagnostic criteria but a 50% risk is a reasonable estimate. Incidence and prevalence of cGVHD are probably growing because of increased use of unrelated donors, blood rather than bone marrow (BM) grafts, decreased early transplant-related mortality (TRM) and increasing frequency of allotransplants. Pathophysiology of cGVHD is complex and poorly understood. Notably, no reliable surrogate end point to predict mechanism(s) of cGVHD has been identified. Therapy of cGVHD is unsatisfactory. Corticosteroids are effective but other drugs are controversial and few are rigorously tested in randomized trials. Highly variable response rates are reported because of small sample sizes and inconsistencies in eligibility, diagnostic and response criteria. We focus on the possible role of immunomodulatory drugs (IMiDs), thalidomide lenalidomide and pomalidomide, in preventing and treating cGVHD. The data suggest activity of thalidomide but at doses not clinically practical in many instances. There are few data with lenalidomide. Trials of pomalidomide, which has immune activities like thalidomide but with fewer adverse effects, are beginning. Because cGVHD is not recently reviewed in Bone Marrow Transplantation, we give a brief background and discuss challenges in diagnosing, understanding and treating cGVHD including the recently proposed National Institutes of Health consensus criteria for cGVHD. 1-3 It occurs in about 50% of persons surviving 41 year post transplant and causes substantial morbidity and mortality. There has been little progress over the past 30 years in preventing and/or treating cGVHD. Moreover, incidence and prevalence are increasing because of several factors including: (1) increased use of blood cell rather than BM grafts; (2) increasing use of incompletely HLA-matched related and unrelated donors; (3) increased use of donor-lymphocyte infusions, especially in the context of reduced-intensity allotransplants; (4) increased number of transplants done each year; and (5) increased proportion of transplants in older persons. [4][5][6] The focus of our review is on the use and potential of IMiD-class drugs to prevent and/or treat cGVHD. These drugs have unique, complex immune regulatory activities. As a prelude, we review some relevant definitional, laboratory and clinical features of cGVHD.

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The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery

Cited by 134 publications

References 30 publications

The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Immune modulation and chronic graft-versus-host disease

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

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