Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab

Lilienfeld‐Toal

et al. 2012

Blood

Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate firstline treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroidrefractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host-as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies. (Blood. 2012;119(1):16-25) IntroductionIn 1957, E. D. Thomas and colleagues first described the infusion of bone marrow cells into patients after prior radio-or chemotherapy in their seminal New England Journal of Medicine paper. 1 This work initiated 5 decades of basic and clinical research in the field of stem cell transplantation (SCT) and nowadays SCT is the treatment of choice for many malignant and benign hematopoietic diseases. It was known before 1957 from preclinical animals studies that tranplantation of splenocytes from noncongenic donor strains, while facilitating hematopoietic recovery, induced a severe illness, characterized by progressive weight loss, hunched posture, and diarrhea. 2 In the following years it has become clear that this was not primarily because of the conditioning therapy, but that it was an immune-mediated syndrome, which is now referred to as graft versus host disease (GVHD). GVHD nowadays remains not only a major cause of non-relapse mortality, but also induces substantial morbidity, which can severely affect quality of life. GVHD is a very complex immunologic disorder characterized by a plethora of clinical presentations. 3 Importantly, the predominant use of peripheral blood stem cells (PBSC) rather than bone marrow (BM) and the increasing proportion of reduced intensity conditioning (RIC) regimens has made multifacetted chronic GVHD (cGVHD) more and more clinically relevant. 4,5 The incidence of GVHD thus depends on several variables, including the donor type (related versus unrelated, matched versus mismatched or haploidentical), the type of conditioning (total boby irradiation [TBI] versus nonTBI), the donor's sex (female or male, versus all other sex combinations) and the stem cell source (PBSC versus BM). 6 Despite the inc...

Section: B-cell Targetingmentioning

confidence: 99%

Novel treatment concepts for graft-versus-host disease

Lilienfeld‐Toal

et al. 2012

Blood

“…[17][18][19] In addition, rituximab also induces downregulation of CD40 and CD80 on B cells, leading to further disturbed T-cell activation. 20,21 Finally, it has been suggested that rituximab may lead to macrophage Fc-receptor blockade by rituximab-opsonized B cells and hence reduction of platelet destruction in the spleen, a mechanism referred to as the "immune complex decoy hypothesis." 22 Barcellini et al 23 investigated…”

Section: How Does Rituximab Work?mentioning

confidence: 99%

The role of rituximab in adults with warm antibody autoimmune hemolytic anemia

Dierickx

Kentos

Delannoy

2015

Blood

Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (∼70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed.

“…Recent studies have addressed flowcytometric changes post-RTX in SLE patients. One study (82) shows down-regulation of CD40 and CD80 involved in the B/T cell interaction in the remaining CD19 þ B cells. Another study (59) showed a fourfold decrease in CD40L on CD4 þ T cells as well as significant decreases in T cell activation markers (CD69 and HLA-DR) and NK cells, whereas overall T cell counts increased (59).…”

Section: Rtx In the Treatment Of Slementioning

confidence: 99%

“…Relevance of RTX for treatment of GD B cell depletion by means of RTX therapy has been proved effective in a large fraction of patients with treatment-resistant autoimmune diseases, including RA (66), SLE (59,81,82) and ITP (86 -88). In addition to being precursor cells for the Ig (and autoantibody)-secreting plasma cells, B cells are also known as critical APCs in AITD (9,10,36,39) and other autoimmune diseases (5 -8), a role which may be partly dependent upon complement and autoantibodies as shown for Tgabs (36,39).…”

Section: Adverse Effects Of Rtx Treatmentmentioning

confidence: 99%

The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option

Fassi¹,

Nielsen²,

Hasselbalch³

et al. 2006

eur j endocrinol

We have reviewed the immunology of thyroid autoimmunity with special reference to the importance of B lymphocytes (B cells) in thyroidal and extrathyroidal Graves' disease (GD), thus providing a framework for the hypothesis that B cell depletion may be beneficial in GD. Additionally, after reviewing the efficacy and safety in other autoimmune diseases, we propose that treatment with the B celldepleting agent Rituximab may become a clinically relevant treatment option in selected cases of GD, particularly when complicated with thyroid-associated ophthalmopathy.European Journal of Endocrinology 154 623-632