Perforin mediates target cell apoptosis by CTLs and NK cells. Although perforin expression correlates strongly with acute allograft rejection, perforin-deficient mice reject allografts with the same kinetics as wild-type recipients. In this study, we tested the hypothesis that while perforin is dispensable for acute rejection, it is essential for down-regulating the alloimmune response by inducing the apoptosis of host immune cells. Using a skin transplantation model, we found that perforin-deficient mice are resistant to the induction of allograft acceptance by agents that block T cell costimulation. Failure to induce allograft acceptance in these mice was observed irrespective of whether the alloimmune response was CD4 or CD8 T cell-mediated and could be attributed to defective apoptosis of activated CD4 and CD8 T cells. In contrast, perforin did not influence T cell proliferation. Therefore, perforin is an essential immunoregulatory molecule that may be required for the induction of transplantation tolerance.
Studies of memory T cell differentiation are hampered by a lack of quantitative models to test hypotheses in silico before in vivo experimentation. We created a stochastic computer model of CD4+ memory T cell generation that can simulate and track 101–108 individual lymphocytes over time. Parameters for the model were derived from experimental data using naive human CD4+ T cells stimulated in vitro. Using discrete event computer simulation, we identified two key variables that heavily influence effector burst size and the persistent memory pool size: the cell cycle dependent probability of apoptosis, and the postactivation mitosis at which memory T cells emerge. Multiple simulations were performed and varying critical parameters permitted estimates of how sensitive the model was to changes in all of the model parameters. We then compared two hypotheses of CD4+ memory T cell generation: maturation from activated naive to effector to memory cells (model I) vs direct progression from activated naive to memory cells (model II). We find that direct progression of naive to memory T cells does not explain published measurements of the memory cell mass unless postactivation expansion of the memory cell cohort occurs. We conclude that current models suggesting direct progression of activated naive cells to the persistent memory phenotype (model II) do not account for the experimentally measured size of the postactivation CD4+, Ag-specific, memory T cell cohort.
Few studies have explored whether the type of LT, deceased donor LT (DDLT) or living donor LT (LDLT), impacts long term renal outcomes. We performed a retrospective analysis of 220 LT recipients at our institution to study their renal outcomes at 10 years. Exclusion criteria were, age ≤18 years, graft survival ≤ 6 months and multiorgan transplants; 108 DDLTs and 62 LDLTs were eligible. At baseline, DDLTs had a lower eGFR than LDLTs and 10.2% of DDLTs were on dialysis as compared to 0% of LDLTs. At 10 years, 7 DDLT and 3 LDLT recipients required dialysis or renal transplant (p=0.75). In recipients with graft survival >6 months, DDLTs had a slower decline in eGFR as compared to LDLTs (p<0.01). Amongst LDLTs the decline in eGFR continued over the entire 10-year period, whereas amongst DDLTs, the decline in eGFR slowed significantly after 6-months (p=0.01). This difference between the two groups was not seen amongst patients in the highest quartile of baseline eGFR. Patient and graft survival was similar. In conclusion, the incidence of end stage renal disease was similar in both DDLT and LDLT patients but LDLT recipients seem to have a more sustained decline in eGFR when compared to DDLT recipients.
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