Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation

Abstract

The accurate evaluation of donor-specific antibodies (DSAs) has allowed a precise identification of sensitized patients at risk of antibody-mediated rejection (ABMR). However, the scale of the humoral response is not always fully addressed, as it excludes the complete memory B-cell (mBC) pool such as that caused by antigen-specific mBC. Using a novel B-cell ELISpot assay approach, we assessed circulating mBC frequencies against class I and II HLA antigens in highly sensitized and nonsensitized patients in the waiting list for kidney transplantation. Also, kidney transplant patients undergoing ABMR were evaluated for the presence of donor-specific mBCs both at the time of rejection and before transplantation. For this purpose, 278 target HLA-sp antigens from 70 patients were studied and compared to circulating HLA-sp antibodies. Both class I and II HLA-sp mBC frequencies were identified in highly sensitized individuals but not in nonsensitized and healthy individuals, many years after first sensitization. Also, high donor-specific mBC responses were clearly found both during ABMR and before transplantation, regardless of circulating DSA. The higher the donor-specific mBC response, the more aggressive the allograft rejection. Thus, assessing donor-specific mBC frequencies may be relevant to better refine patient alloimmune-risk stratification, and provides new insight into the mechanisms of the adaptive humoral alloimmune response taking place in kidney transplantation.

Biomarkers to assess donor-reactive T-cell responses in kidney transplant patients

“…Of note, this has been possible due to the accurate characterization of the humoral allogeneic immune response using novel and highly sensitive techniques for monitoring alloimmune sensitization against donor HLA antigens (7)(8)(9). However, the assessment of the global immune risk in transplant patients still remains incomplete as it excludes a main effector mechanism of adaptive immunity which is that driven by alloreactive T-cells.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…On the other hand, patients with a known history of sensitization events may not exhibit detectable circulating anti-HLA antibodies at the time of transplant evaluation. This has prompted development of alternative methods to measure alloreactivity, including an HLA-specific B cell enzyme-linked immunospot (ELISPOT) (63,64), ex vivo stimulation of B cells (65,66), and staining of peripheral B cells with HLA tetramers (67). More work is needed to understand the clinical relevance of alloreactive memory B cells in the absence of circulating HLA DSAs.…”

Immune Tolerance for Autoimmune Disease and Cell Transplantation

“…However, in addition to such humoral sensitization, cellular sensitization is also a significant barrier. Allospecific memory T cells can mount robust antidonor responses even with minimal costimulation signals, and memory B cells may be capable of rapidly developing into antibody-secreting plasma cells even in the absence of T cell help (104, 105). These “shortcuts” frequently evade and nullify conventional tolerance mechanisms, and may additionally turn a donor cell–based tolerance therapy into an exacerbating event.…”