INTRODUCTION. What determines whether alloantibody mediates acute or chronic allograft rejection remains unclear; here we examine the role of CD4 T cell help.
METHODS. BALB/c hearts were transplanted into T cell-deficient (TCR-/-) C57BL/6 recipients and control C57BL/6 Rag2-/- recipients lacking T and B cells. T cell help was provided by transfer of either high (105 cells) or low (103 cells) numbers of TCR-transgenic TCR75 CD4 T cells that recognise MHC class I donor H2-Kd antigen as processed peptide via the indirect pathway. Alloantibody production was determined by anti-H-2Kd ELISA.
RESULTS. TCR-/- recipients reconstituted with 105 TCR75 T cells rejected BALB/c hearts acutely (MST 9 days, n=10), with rapid production of high alloantibody titres. In contrast, heart grafts survived for > 50 days in similarly-reconstituted control Rag2-/- recipients, with confirmation of an effector role for alloantibody provided by the restoration of acute heart graft rejection in Rag2-/- mice following passive transfer of immune serum from the reconstituted-TCR-/- recipients. Although rejection in reconstituted TCR-/- recipients was associated with a splenic Germinal Centre (GC) reaction, GC responses were not detectable until after rejection, suggesting that strong extrafollicular responses driven by high T cell numbers are sufficient to mediate acute humoral rejection.
Reconstitution of TCR-/- recipients with 103 CD4 T cells resulted in initially lower alloantibody titres, which nevertheless increased gradually, with development of progressive allograft vasculopathy and eventual graft failure (MST 50 days, n=8). This rejection is likely due to chronic alloantibody-mediated damage, because endothelial complement deposition was readily evident and because heart grafts survived indefinitely, without complement deposition and with minimal vasculopathy, in T cell-reconstituted Rag2-/- recipients (n=5). Antibody levels increased concomitant with the development of splenic GCs suggesting that small helper T cell numbers generate weak extrafollicular responses that are insufficient to drive acute rejection, but can nevertheless provide help for the development of late GC responses that can effect chronic humoral rejection.
CONCLUSION. In this novel model of humoral rejection, the development of acute or chronic heart graft rejection is determined by the magnitude of the alloantibody response, which in turn is determined by the availability of T cell help.
To cite this abstract in AMA style:Chhabra M, Callaghan C, Negus M, Rehakova S, Qureshi S, Bolton E, Bradley J, Pettigrew G. T Cell Help Is Critical in Determining Mode of Alloantibody-Mediated Allograft Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/t-cell-help-is-critical-in-determining-mode-of-alloantibody-mediated-allograft-rejection/. Accessed September 23, 2017.
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