In our studies of life-supporting GalT-KO pig-to-baboon kidneys, we have found that some recipients developed increased serum creatinine with growth of the grafts, without histologic or immunologic evidence of rejection. We hypothesized that the rapid growth of orthotopic pig grafts in smaller baboon recipients may have led to deterioration of organ function. To test this hypothesis for both kidneys and lungs, we have assessed whether the growth of outbred (Yorkshire) organ transplants in miniature swine is regulated by intrinsic (graft) or extrinsic (host environment) factors. Yorkshire kidneys exhibited persistent growth in miniature swine, reaching 3.7x their initial volume over 3 months vs. 1.2x for miniature swine kidneys over the same time period. Similar rapid early growth of lung allografts was observed and, in this case, led to organ dysfunction. For xenograft kidneys, a review of our results suggests that there is a threshold of 25cm3/kg for kidney graft volume/recipient body weight that induces cortical ischemia in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are responsible, at least in part, for growth of donor organs and that this property should be taken into consideration for growth-curve mismatched transplants, especially for life-supporting organs transplanted into a limited recipient space.
We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival.
To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.
Regulatory T cells (Treg) play an important role in modulating the immune response and has attracted increasing attention in diverse fields such as cancer treatment, transplantation and autoimmune diseases. CC chemokine receptor 4 (CCR4) is expressed on the majority of Tregs, especially on effector Tregs. Recently we have developed a diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4+ cells in vivo. In this study, we demonstrated that the anti-human CCR4 immunotoxin bound and depleted monkey CCR4+ cells in vitro. We also demonstrated that the immunotoxin bound to the CCR4+Foxp3+ monkey Tregs in vitro. In vivo studies performed in two naive cynomolgus monkeys revealed 78–89% CCR4+Foxp3+ Treg depletion in peripheral blood lasting approximately 10 days. In lymph nodes, 89–96% CCR4+Foxp3+ Tregs were depleted. No effect was observed in other cell populations including CD8+ T cells, other CD4+ T cells, B cells and NK cells. To our knowledge, this is the first agent that effectively depleted non-human primate (NHP) Tregs. This immunotoxin has potential to deplete effector Tregs for combined cancer treatment.
Histopathological changes of acute vascular rejection (AVR) are characterized by intimal arteritis and transmural arteritis. According to the Banff 1997 classification, the quantitative criteria for intimal arteritis (v score) are classified: v0, v1, v2, and v3. According to Banff ‘09 classification, AVR may fall into one of four categories: acute T cell‐mediated rejection (ATMR) Type IIA, ATMR Type IIB, ATMR Type III, and acute antibody‐mediated rejection (AAMR) Type III.
Both cellular and humoral immunity play roles in vascular rejection, and in some cases, AVR may be provoked by anti‐donor antibodies. Anti‐rejection therapies were effective in most of the v1 cases but were less effective in the v2 cases and were ineffective in the v3 cases. Some reports have indicated that the prognosis of grafts exhibiting AVR is poor, but in our series, the outcome of AVR was relatively good using recent immunosuppressive protocols.
A definition for “isolated v‐lesion” was originally characterized by arteritis with minimal interstitial inflammation and tubulitis. The 11th Banff conference was concluded that “isolated v1‐lesions” comprised two types, T cell‐mediated rejection and injury, and did not have any independent prognostic significance. However, we speculate that “isolated v‐lesion” might be regarded as AAMR and ATMR.
Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.
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