Donor-reactive memory T cells are a significant hurdle to successful organ transplantation. We showed that memory CD4 T cells induced anti-donor effector CD8 T cells and alloantibody (alloAb) that in turn mediated graft destruction in mouse models. Recipients with memory CD4 T cells reject cardiac allografts despite treatment with anti-CD154 mAb, with the graft injury primarily inflicted by CD8 T cells.
The goal of this study was to evaluate the functions of donor-reactive memory CD4 T cells in murine renal allograft recipients. B6 (H-2b) recipients spontaneously accept A/J (H-2a) kidney allografts for >60 days with low level cellular and humoral anti-donor responses. Previous sensitization with A/J skin allografts leads to rapid rejection of kidney transplants characterized by intensive T cell infiltrate and Ab-mediated injury.
To focus on the role of donor-reactive memory CD4 T cells, CD4+CD44hi cells were isolated from A/J skin sensitized B6 recipients or naÏve B6 mice and injected into naÏve B6 mice followed by A/J renal transplantation. Control recipients injected with memory CD4 T cells from naÏve B6 mice preserved renal graft function for >40 d. In contrast, all recipients containing A/J sensitized memory CD4 T cells had a rapid rise of serum creatinine over 1 mg/dl (< 0.4 mg/dl in non-transplanted mice) and had to be sacrificed (MST of 7 d, n=9). These recipients had high titers of A/J-specific IgG Ab (10-50 fold increase compared to unmanipulated B6 recipients). Immunohistochemical staining of graft tissue revealed diffuse deposition of C4d complement component in capillaries and cellular infiltrates consisted mainly of macrophages with few CD3+ cells. Thus, the graft loss was consistent with all diagnostic criteria for renal Ab-mediated rejection: 1) increased serum creatinine levels; 2) high serum titers of anti-donor Ab; 3) histological evidence of acute tissue injury; 4) complement component deposition. In support of the hypothesis that alloAb and not T cells are the dominant effector mechanism of graft rejection in this model, depletion of recipient CD8 T cells did not alter the kinetics of rejection (MST of 6 d, n=2).
Taken together, these results show that in contrast to previously characterized model of heart transplantation, memory CD4 T cells cause renal allograft rejection primarily through induction of pathogenic alloAb rather than through providing help for effector CD8 T cells.
To cite this abstract in AMA style:Gorbacheva V, Fan R, Baldwin W, Valujskikh A. Donor-Reactive Alloantibodies Are the Dominant Effector Mechanism of Murine Kidney Allograft Rejection Induced by Memory CD4 T Cells [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/donor-reactive-alloantibodies-are-the-dominant-effector-mechanism-of-murine-kidney-allograft-rejection-induced-by-memory-cd4-t-cells/. Accessed April 15, 2021.
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