Cryptic B Cell Response to Renal Transplantation

Abstract

Renal transplantation reliably evokes allo-specific B cell and T cell responses in mice. Yet, human recipients of kidney transplants with normal function usually exhibit little or no antibody specific for the transplant donor during the early weeks and months after transplantation. Indeed, the absence of anti-donor antibodies is taken to reflect effective immunosuppressive therapy and to predict a favorable outcome. Whether the absence of donor-specific antibodies reflects absence of a B-cell response to the donor, tolerance to the donor or immunity masked by binding of donor-specific antibodies to the graft is not known. To distinguish between these possibilities, we devised a novel ELISPOT, using cultured donor, recipient and third-party fibroblasts as targets. We enumerated donor-specific antibody-secreting cells in the blood of nine renal allograft recipients with normal kidney function before and after transplantation. Although none of the nine subjects had detectable donor-specific antibodies before or after transplantation, all exhibited increases in the frequency of donor-specific antibody-secreting cells eight weeks after transplantation. The responses were directed against the donor HLA-class I antigens. The increase in frequency of donor-specific antibody-secreting cells after renal transplantation indicates that B cells respond specifically to the transplant donor more often than previously thought.

Polyclonal B cell activation for accurate analysis of pre-existing antigen-specific memory B cells

“…While serum antibodies are produced mainly by bone marrow-residing plasma cells [26,27], their serum levels may not be representative for the peripheral memory B cell pool. Indeed, Lynch et al recently showed the presence of donor-specific memory B cells in the absence of donor-specific serum IgG antibodies in kidney transplant recipients [12]. These, and other data [11], made clear that in-vitro polyclonal B cell activation may be used to provide a snapshot of the B cell memory pool at a given time-point.…”

“…Our group has recently developed an HLA-specific B cell enzyme-linked immunospot (ELISPOT) assay which allows for the quantification of memory B cell frequencies directed towards defined HLA molecules [11]. This technique was recently adapted by Lynch and colleagues to detect B cell memory towards donor-specific HLA class I on cultured fibroblasts from donor origin [12].…”

Immune response and histology of humoral rejection in kidney transplantation

“…But, surprisingly, although the detection technique has been perfected, 26 the presence of antibodies against HLA antigens is low in the first phase of transplantation, despite immunosuppressive therapy that is more effective against T cells than B cells. Some have interpreted this as a reflection of the lack of a B-cell response to allogeneic stimulation, 27 and others as the possibility that the response is higher and that antibodies are absorbed and cleared by the allograft. 28 A more direct procedure for assessing allogeneic humoral response by calculating the frequency of antibody-secreting B cells using the ELISPOT technique has been proposed.…”

From Donor to Recipient: Current Questions Relating to Humoral Alloimmunization

“…In humans, B cell recognition consistently occurs early after the graft, despite immunosuppression, without triggering an alloimmune response and rejection [98], but the regulatory activities of these clusters needs more investigation. Finally, the CD40 pathway has been proven necessary to activate the alloimmune adaptive system, but its absence protects from rejection [99,100].…”

“…Indeed, cryptic allospecific reactions are detected in stable grafts in early days without acute rejection [98], suggesting that all patients develop a specific regulatory network, though insufficient for avoiding rejection.…”