Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis

Abstract

A unique characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC) is the presence of high-titer and extremely specific autoantibodies to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Autoantibodies to PDC-E2 antigen have only been detected in patients with disease or in those who subsequently develop PBC. One exception has been a subgroup of patients with multiple myeloma (MM) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received donor lymphocyte infusions (DLIs) after transplantation. These patients developed high-titer antibodies to a variety of myeloma-associated antigens, including PDC-E2, coincident with rejection of myeloma cells in vivo. To examine the specificity of autoantibodies to PDC in these patients, we screened sera from patients with MM, chronic leukemias, monoclonal gammopathy of unknown significance (MGUS), PBC, and healthy donors. Three of 11 patients with MM (27%) and 2 of 6 patients with chronic leukemias (33%) developed anti-PDC-E2 antibodies in association with DLI response; 2 of 12 (17%) patients in the MGUS pretreatment control population also had detectable anti-PDC responses. Interestingly, the epitope specificity of these PDC-E2 autoantibodies was distinctive, suggesting that the mechanisms leading to loss of tolerance in the transplantation patients are distinct from PBC. (Blood.

Graft-versus-Leukemia Antigen CML66 Elicits Coordinated B-Cell and T-Cell Immunity after Donor Lymphocyte Infusion

“…Studies in patients and mouse models have firmly established allo-antigens as an important antigen class targeted by GvL, but mounting evidence suggests that tumor-associated antigens elicit at least part of this response (7–12). We therefore focused our analysis on immune responses directed against CML66.…”

Evidence of B Cell Immune Responses to Acute Lymphoblastic Leukemia in Murine Allogeneic Hematopoietic Stem Cell Transplantation Recipients Treated with Donor Lymphocyte Infusion and/or Vaccination

“…Monoclonal anti-CD20 has a clear role in the treatment of B lineage lymphomas (17, 18). Antibodies to minor histocompatibility antigens and nonpolymorphic hematopoietic antigens have been identified in some studies of human graft versus host disease (19–22), especially chronic graft versus host disease (23, 24). Active chronic graft versus host disease has been associated with evidence of B cell activation (25, 26).…”

“…Following 800 cGy TBI (given in two equal divided doses 14–16 hours apart) and ip 5-fluoruracil (0.5 mg) C57BL/6 recipients were infused with 4 × 10 6 marrow cells plus 10 × 10 6 splenocytes from normal C57BL/6 mice or C3.SW mice immunized against C57BL/6 splenocytes (20–22). They were housed in conventional rooms with food and water ad libitum.…”

Bone marrow findings in patients with autoimmune liver diseases

“…Under this context, AIH has been associated with acquired pure red cell aplasia (erythroblastopenia) cured by cyclophosphamide, 7 whereas PBC has been associated with idiopathic myelofibrosis 8 . In contrast, antimitochondrial antibodies (AMA) against the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2), which is a unique characteristic of PBC, have also been detected in a subgroup of multiple myeloma patients who underwent allogeneic hematopoietic stem cell transplantation and received donor lymphocyte infusions, supporting the well‐known association between B‐cell neoplasms and autoimmunity 9 . In addition, Milkiewicz et al .…”

“…8 In contrast, antimitochondrial antibodies (AMA) against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), which is a unique characteristic of PBC, have also been detected in a subgroup of multiple myeloma patients who underwent allogeneic hematopoietic stem cell transplantation and received donor lymphocyte infusions, supporting the well-known association between B-cell neoplasms and autoimmunity. 9 In addition, Milkiewicz et al recently reported a small study of five patients who had suffered from hematological neoplasms and had acquired autoimmune liver diseases. 10 activation and the production of cytokine suppressors of hematopoiesis in long-term cultures of BM mononuclear cells from patients with AIH type-1 (AIH-1) and PBC compared to healthy individuals and patients with cirrhosis of non-autoimmune etiology.…”