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Histologic evaluation of allograft biopsies after lung transplantation has several limitations, suggesting that molecular assessment using tissue transcriptomics could improve biopsy interpretation. This single-center, retrospective cohort study evaluated discrepancies between the histology of transbronchial biopsies (TBBs) with no rejection (NR) and T-cell mediated rejection (TCMR) by molecular diagnosis. The accuracy of diagnosis was assessed based on response to treatment. 54 TBBs from Prague Lung Transplant Program obtained between December 2015 and January 2020 were included. Patients with acute cellular rejection (ACR) grade = 1 by histology received anti-rejection treatment. Response to therapy was defined as an increase in FEV1 of = 10% 4 weeks post-biopsy compared to the pre-biopsy value. Among the 54 analyzed TBBs, 25 (46%) were concordant with histology, while 29 (54%) showed discrepancies. ACR grade 0 was found in 12 TBBs (22%) and grade A1 = 1 in 42 TBBs (78%). Treatment response was present in 14% in the NR group and in 50% in the TCMR group (p = 0.024). Our findings suggest that low-grade acute cellular rejection is less likely to be associated with molecular TCMR, which might better identify lung transplant recipients who benefit from therapy. [ABSTRACT FROM AUTHOR]

Examines the role of interferon (IFN)-gamma in allograft rejection. Biological functions of IFN-gamma; Overview of the events in an organ transplantation; Characteristics of the alloimmune response; Immune mechanisms that may be used in approaching organ allograft rejection; Description of IFN-gamma; Types of transcription factors that are regulated by IFN-gamma.

The effects of anti-immunoglobulin (anti-Ig) on the susceptibility of mouse B cell or alloantibody-coated thymocytes to lysis by human K cells were studied. Since anti-Ig caps readily, we examined in particular the relationship between the extent of capping of the target cells and their susceptibility to lysis by K cells. The effects varied with the anti-Ig concentration: dilute anti-Ig capped B cells poorly and induced K cell lysis very efficiently. Dilute anti-Ig could also augment alloantibody-induced ADCC: for example. anti-Thy-1 coated thymocytes, which were not lysed by K cells in the absence of anti-Ig, could be lysed extensively when dilute anti-Ig was present. High anti-Ig concentrations induced more extensive capping and less K cell lysis than more dilute anti-Ig, suggesting that capping does reduce susceptibility to K cells. Nevertheless, when the ability of K cells to lyse anti-Ig-coated targets was compared to that of complement, K cells were superior in two respects: (i) K cell lysis could be induced by low (subcapping) concentrations of anti-Ig, whereas complement lysis could not; and (ii) K cells could lyse even extensively capped targets to some extent, whereas such targets were highly resistant to complement. We conclude that (i) augmentation of ADCC by dilute anti-Ig can be demonstrated and may be useful in systems in which the first antibody induces ADCC poorly; and (ii) the K cell system could have a particular role in vivo in the lysis of antibody-coated cells or micro-organisms which cap readily. [ABSTRACT FROM AUTHOR]

In earlier studies on rodents it was established that macrophages could have either destructive or protective effects on antibody-coated nucleated cells. The present studies were initiated to determine which of these effects predominated with human macrophages. Macrophage-rich peritoneal cell suspensions from peritoneal dialysis fluid were incubated with alloantibody-coated human lymphocyte target cells. The lymphocytes were not lysed, although as expected the peritoneal cells could lyse or phagocytize antibody-coated human erythrocytes. Nevertheless, the peritoneal cells did interact vigorously with the lymphocyte target cells, since the latter rapidly became resistant to lysis by complement. Such resistance was not due to engulfment of whole target cells by macrophages, since the target cells could still be lysed by complement when a second antibody was added. The development of resistance to complement lysis was a temperature- and time-dependent, Fc receptor mediated effect of adherent cells, and was inhibitable by cytochalasin B and various metabolic inhibitors. These results indicate that the principal action of human macrophages on antibody-coated nucleated human cells is inactivation or removal of the antibody bound to the target cell membrane, resulting in protection of the target cells from antibody-dependent destruction. However, it is possible that the observed protection was produced only at the expense of subtle, non-lethal membrane damage, since small but significant increases in osmotic fragility of the target cells were frequently demonstrable after incubation with macrophages. [ABSTRACT FROM AUTHOR]

BACKGROUND Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option. METHODS In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels. RESULTS A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. After week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donorderived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibodymediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. CONCLUSIONS Felzartamab had acceptable safety and side-effect profiles in patients with antibodymediated rejection. [ABSTRACT FROM AUTHOR]

The cell cycle inhibitor p16INK4A (also known as cyclin-dependent kinase inhibitor 2A) is expressed in vivo in many tissues with age. The exposure of certain chronic stresses can trigger p16INK4A expression and a senescence-like phenotype. We studied whether p16INK4A expression is induced in glomerular disease (GD). We performed p16INK4A immunostaining on 35 biopsies with GD, 12 tubulointerstitial nephritis (TIN), and 19 normal live donor kidneys at transplantation. Based on values for 42 normal kidneys, we calculated expected nuclear p16INK4A expression for age and compared the observed values in diseased kidneys to those expected for age. In GD, p16INK4A expression was strikingly increased in glomerular and interstitial cell nuclei compared to normals and TIN, and could not be attributed to age (P<0.05). By multivariate analyses, GD was independently associated with increased nuclear p16INK4a expression in glomeruli (P<0.001) and interstitium (P=0.01). The p16INK4A expression in glomerular and interstitial cell nuclei, and tubular cytoplasm was higher in kidneys with proteinuria and with atrophy/fibrosis (P<0.05). Older age was associated with increased nuclear p16INK4a expression in tubules (P=0.01), and interstitial inflammation was associated with increased nuclear p16INK4a expression in interstitial cells (P=0.001). The p16INK4a staining in tubular cytoplasm was increased in both GD and TIN compared to normals (P<0.001), and was not related to age (P>0.05). Thus, kidneys with GD display increased expression of senescence marker p16INK4A in glomerular and interstitial cell nuclei compared to kidneys with normal aging or TIN. The findings suggest a role for somatic cell senescence mechanisms in progression of GD.Kidney International (2007) 71, 218–226. doi:10.1038/sj.ki.5002039; published online 20 December 2006 [ABSTRACT FROM AUTHOR]