Key Role for CD4 T Cells During Mixed Antibody-Mediated Rejection of Renal Allografts

Abstract

We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated anti-donor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating anti-donor alloantibody responses.

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

“…Given that IFN‐γ and IL‐4 are of great importance in driving Mφ to M1 and M2 polarization and enhancing their activities, triptolide remarkably reduced mRNA expression levels of both IFN‐γ and IL‐4, implying that triptolide inhibits macrophage‐mediated responses by synergistically reducing their numbers as well as their functional enhancers. In addition, increased infiltration of CD8 + T cells in graft had also been documented to be correlated with AMR in heart grafts, with the ratio of CD4 + /CD8 + T cells significantly shifting to CD8 + T cells compared to cell‐mediated rejection, and CD4 + T cells played a key role in the AMR disease model . Accordingly, our results found in this model that the frequencies and numbers of CD8 + T cells and CD8 + IFN‐γ + cells and CD49b + NK cell numbers were significantly reduced in grafts with triptolide treatment.…”

One-year Results of the Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Transplantation

“…In these mixed cellular rejections, the use of a T-cell-depleting agent could be considered, as previously proposed, and needs to be assessed in future trials. 43 Nevertheless, as in autoimmunity, rituximab often takes a number of months to work; we noted that at 12 months, the number of patients with iDSAs less than 1 500 was more frequent in the rituximab group than the placebo group. Decreased microvascular inflammation was observed in the rituximab group between rejection and 6 months, and increased chronic lesions was significant only in the placebo group.…”

Antibodies to HLA Molecules Mimic Agonistic Stimulation to Trigger Vascular Cell Changes and Induce Allograft Injury

“…Interestingly, rapamycin treatment of endothelial cells resulted in selective expansion of Tregs via PD-L1 and PD-L2 [8•], suggesting that mTOR regulates endothelial alloimmunogenicity. These novel T cell interactions are relevant to antibody-mediated rejection, as the role of CD4 cells in so-called “mixed” AMR is increasingly reported in experimental models [79]. It has also been proposed that HLA antibodies may modulate endothelial immunogenicity [6••], a fascinating avenue of investigation that remains to be fully illuminated.…”