Tree-in-bud sign

Abdominal Radiology -     

The hyperdense crescent sign

Abdominal Radiology -     

Modulation of human lymphocyte proliferation by FLFQPQRFamide, a FMRFamide-like peptide with anti-opiate properties.

The octapeptide Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F8Fa), originally detected in mammalian brain by antisera raised against the invertebrate peptide Phe-Met-Arg-Phe-NH2 (FMRFamide) is a neuropeptide able to antagonize the actions of both endogenous and exogenous opiates. Since it is well accepted that lymphocytes are targets for opiates, we have tested the effect of F8Fa on T cell proliferation from normal human peripheral blood lymphocytes. Our study shows that F8Fa exerts a concentration-dependent diphasic modulation of human T lymphocyte proliferation. Thus, despite a great variability between individuals, 10(-13) M F8Fa was found to enhance the proliferation of T cells induced by phytohemagglutinin or anti-CD2 monoclonal antibodies, while 10(-7) M F8Fa inhibited T cell proliferation, without affecting cell viability. When F8Fa was tested on monocyte-depleted cell preparations, only the inhibitory effect was observed. These results indicate that F8Fa may stimulate T cells via monocytes, but may also directly inhibit T lymphocyte proliferation. Given the presence of F8Fa-like peptide in human plasma, we suggest that F8Fa may act as a neurohormone in the control of the immune system.     

Interleukin‐7 receptor blockade by an anti‐CD127 monoclonal antibody in nonhuman primate kidney transplantation

IL‐7 is an important cytokine for T cell lymphopoiesis. Blockade of the IL‐7 signaling pathway has been shown to induce long‐term graft survival or graft tolerance in murine transplant models through inhibiting T cell homeostasis and favoring immunoregulation. In this study, we assessed for the first time the effects of a blocking anti‐human cluster of differentiation 127 (CD127) mAb administered in combination with low‐dose tacrolimus or thymoglobulin in a life‐sustaining kidney allograft model in baboons. Contrary to our expectation, the addition of an anti‐CD127 mAb to the treatment protocols did not prolong graft survival compared to low‐dose tacrolimus alone or thymoglobulin alone. Anti‐CD127 mAb administration led to full CD127 receptor occupancy during the follow‐up period. However, all treated animals lost their kidney graft between 1 week and 2 weeks after transplantation. Unlike in rodents, in nonhuman primates, anti‐CD127 mAb treatment does not decrease the absolute numbers of lymphocyte and lymphocyte subsets and does not effectively inhibit postdepletional T cell proliferation and homeostasis, suggesting that IL‐7 is not a limiting factor for T cell homeostasis in primates.     

Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3(+) )-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates

Lymphocyte-activation gene-3 (LAG-3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG-3(+) T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti-LAG-3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG-3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non-human primate model of delayed-type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)-activated CD4(+) and CD8(+) human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0·1 mg/kg was sufficient to deplete LAG-3(+) -activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)-driven skin inflammation in a tuberculin-induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long-lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG-3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.     

Xenotransplantation of galactosyl-transferase knockout, CD55, CD59, CD39, and fucosyl-transferase transgenic pig kidneys into baboons

Galactosyl-transferase knockout (GT-KO) pigs represent the latest major progress to reduce immune reactions in xenotransplantation. However, their organs are still subject to rapid humoral rejection involving complement activation requiring the ongoing development of further genetic modifications in the pig. In a pig-to-baboon renal transplantation setting, we have used donor pigs that are not only GT-KO, but also transgenic for human CD55 (hCD55), hCD59, hCD39, and fucosyl-transferase (hHT). We studied kidney xenograft survival, physiological and immunologic parameters, xenogeneic rejection characteristics, as well as viral transmission aspects among two groups of baboons: control animals (n = 2), versus those (n = 4) treated with a cocktail of cyclophosphamide, tacrolimus, mycophenolate mofetil, steroids, and a recombinant human C1 inhibitor. Whereas control animals showed clear acute humoral rejection at around day 4, the treated animals showed moderately improved graft survival with rejection at around 2 weeks posttransplantation. Biopsies showed signs of acute vascular rejection (interstitial hemorrhage, glomerular thrombi, and acute tubular necrosis) as well as immunoglobulin (Ig)M and complement deposition in the glomerular and peritubular capillaries. The low level of preformed non-Gal-α1.3Gal IgM detected prior to transplantation increased at 6 days posttransplantation, whereas induced IgG appeared after day 6. No porcine endogenous retrovirus (PERV) transmission was detected in any transplanted baboon. Thus, surprisingly, organs from the GT-KO, hCD55, hCD59, hCD39, and hHT transgenic donors did not appear to convey significant protection against baboon anti-pig antibodies and complement activation, which obviously continue to be significant factors under a suboptimal immunosuppression regimen. The association, timing, and doses of immunosuppressive drugs remain critical. They will have to be optimized to achieve longer graft survivals.