Evidence for Humoral Rejection of a Pancreatic Islet Graft and Rescue with Rituximab and IV Immunoglobulin Therapy

Abstract

We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex R screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex R tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free.

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

“…Reports that short-term T-cell-specific immunosuppression prevented the antibody response against transplanted MSCs support the hypothesis of a T-cell-driven humoral response against cellular grafts (Poncelet et al, 2008). Ongoing humoral rejection of islet grafts was successfully treated with an anti-CD20 monoclonal antibody (Kessler et al, 2009). Epitope spreading might have caused some concomitant increase of non-hESC-specific antibodies in our study and has also been recognized after clinical hematopoietic stem cell transplantation (Leffell et al, 2009;Papassavas et al, 2002).…”

Anti-HLA antibodies in regenerative medicine stem cell therapy

“…The development of de novo antibodies against HLA I and II molecules was also reported after failed islet transplantation [35]. The rescue with Rituximab and intravenous immunoglobulin therapy suggested evidence for the clinical relevance of these de novo antibodies [33]. Indeed, the degree of activation of the recipient's immune system may create potent and occasionally insurmountable barriers to successful islet engraftment.…”

“…Indeed, the importance of antibody-mediated rejection after cell transplantation is gaining increasing awareness. Donor-specific-antibodies (DSA) against both HLA and non-HLA epitopes after administration of allogenic cells to restore or repair various tissues have been identified [32][33][34]. It is clear that as cellular therapies move to the clinic it will be essential to monitor recipients to establish whether they become sensitized and how sensitization influences the clinical course of the therapy.…”

Noninvasive Imaging Techniques in Islet Transplantation

“…Current routine immune monitoring is based on the assessment of alloimmune [10] and autoimmune antibodies [11] reflecting only humoral immunity. Moreover, whereas the importance of anti-HLA antibodies is emerging as a factor of islet graft loss [12], the significance of autoantibodies is unclear, as their correlation with clinical outcomes is not well documented [6]. Cellular immunity monitoring appears to be of greater interest, but cell-based assays are more difficult to set up and are currently under experimental investigation [13].…”