The role of B cells in solid organ transplantation

Abstract

The role of antibodies in chronic injury to organ transplants has been suggested for many years, but recently emphasized by new data. We have observed that when immunosuppressive potency decreases either by intentional weaning of maintenance agents or due to homeostatic repopulation after immune cell depletion, the threshold of B cell activation may be lowered. In human transplant recipients the result may be donor-specific antibody, C4d+ injury, and chronic rejection. This scenario has precise parallels in a rhesus monkey renal allograft model in which T cells are depleted with CD3 immunotoxin, or in a CD52-T cell transgenic mouse model using alemtuzumab to deplete T cells. Such animal models may be useful for the testing of therapeutic strategies to prevent DSA. We agree with others who suggest that weaning of immunosuppression may place transplant recipients at risk of chronic antibody-mediated rejection, and that strategies to prevent this scenario are needed if we are to improve long-term graft and patient outcomes in transplantation. We believe that animal models will play a crucial role in defining the pathophysiology of antibody-mediated rejection and in developing effective therapies to prevent graft injury. Two such animal models are described herein.

Fig. 1

The effect of immunosuppressants currently used in transplantation on B cell. Most of conventional immunosuppressants designed to target T-cells, however, B-cell activation is tightly regulated by T-cells, suggesting that suppression of T-cells could have an effect on B-cells as well. The effect of these conventionally used drugs on B-cell function has not been fully elucidated.

Fig. 2

Graft survival and post-transplant graft function in BALB.B to C57BL/6 heart transplantation. Cardiac allograft survival (A) and post-transplant graft function (B) were monitored daily by palpation. 50% of spontaneous graft acceptance was observed from BALB.B to C57BL/6 cardiac allograft model. In these long-term surviving allografts showed decreased beating qualities (cardiac impulses) to <2+ between post-transplant 10–30 days, but beating qualities recovered to 3–4+ and maintained. Anti-LFA-1mAb treated recipients showed no acute rejection and no compromised beating quality.

Fig. 3

Serum alloantibody production and chronic rejection development in alemtuzumab treated CD52Tg mice. (A) Elevated alloantibody production at 10 weeks post transplantation with CR-developed recipients (*p < 0.05). (B) Histologic and immunohistochemical eveidence of antibody-mediated chronic rejection. Slides prepared of post-transplant day 100 cardiac allograft with Elastic, trichrome, and C4d. (a) Elastic staining shows increased neo-intimal hyperplasia in the coronary artery. (b) Trichrome staining reveals higher pathological grades in fibrosis indicated in blue. (c) Immunoperoxidase demonstrates diffuse deposits of C4d (dark brown) in the capillary and arterial endothelium (inset) in a section from a cardiac allograft from C57BL/6 to CD52Tg recipient with alemtuzumab treatment at day 100.

Fig. 4

Gating strategy for allospecific B cells. Lymphocytes were selected for CD4/8/F4-80⁻ and far yellow⁻ (dead cells) cells. B cells were separated as CD19⁺ syngeneic tetramer⁻ and were further gated against allospecific tetramer Tet B (H-2^b) and IgD.