CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 ...(LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans.
We conducted a clinical trial in stable liver transplant recipients 2–6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (ClinicalTrials.gov NCT02949492). One month after LDIL-2 was initiated, those exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months.
All participants achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression.
The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance.
The study is registered at ClinicalTrials.gov (NCT02949492).
The administration of low-dose IL-2 is an effective way of increasing the number of circulating regulatory T cells (Tregs), an immunosuppressive lymphocyte subset that is key for the establishment of immunological tolerance, but its use to promote allograft tolerance in the setting of clinical liver transplantation had not been explored before. In liver transplant recipients on tacrolimus monotherapy, low-dose IL-2 effectively expanded circulating Tregs but did not increase the number of Tregs with donor specificity, nor did it promote their trafficking to the transplanted liver. Low-dose IL-2 did not facilitate the discontinuation of tacrolimus and elicited, as an off-target effect, an IFNγ-orchestrated inflammatory response in the liver that resembled T cell-mediated rejection. These results, supporting an unexpected role for IL-2 in regulating the immunogenicity of the liver, highlight the need to carefully evaluate systemic immunoregulatory strategies with investigations that are not restricted to the blood compartment and involve target tissues such as the liver.
Display omitted
•We aimed to determine the capacity of low-dose IL-2 to promote allograft tolerance in individuals on tacrolimus monotherapy.•Low-dose IL-2 expanded circulating Tregs but did not increase donor-specific Tregs or promote their trafficking to the liver.•Treatment elicited an IFNγ-orchestrated inflammatory response in the liver with accumulation of lympho-monocytic cells in sinusoidal areas.•Low-dose IL-2 was not conducive to liver allograft tolerance and may have increased the risk of T-cell-mediated rejection.
Background
Meckels diverticulum (MD) causes a number of acute surgical pathologies and can contain ectopic tissue with the surgical aim to resect all ectopic mucosa. This has traditionally implied a ...small bowel resection (BR); though contemporary literature has demonstrated Meckel's diverticulectomy to be safe. The aim of this study was to determine optimal resection strategy, and assess MD histopathological features and their relationship to outcomes.
Methods
A 19‐year retrospective review of patient medical records across seven hospitals was conducted with demographic, clinical and pathological data collected. Analysis was conducted using a student's t‐test for continuous variables and chi‐squared test for categorical variables. Univariate regression was performed to identify risk factors. P < 0.05 was considered statistically significant.
Results
One hundred and sixty patients underwent resection of MD, 70 (44%) had Meckel's diverticulectomy and 90 (56%) had BR. No significant difference in length (P = 0.486), width (P = 0.238), or ratio (P = 0.188) of diverticulectomy compared to BR, with fewer complications in diverticulectomy. In all, 24 (15.3%) MD were perforated, of whom 5 had gastric mucosa, 2 had mixed ectopic mucosa and 1 carcinoid tissue. There were no cases of ectopic mucosa in the resection margin requiring re‐operation, or causing base perforation. MD specimen with greater length: width ratio was a risk factor for perforation OR 1.437 P = 0.042 but not for malignancy P = 0.813 or ectopic tissue P = 0.185.
Conclusion
Meckel's diverticulectomy is safe via laparoscopic or open approach compared with BR. Despite higher perforation rates in MD with greater length: width ratio, no malignancy or ectopic risk was identified, supporting diverticulectomy as a safe operative approach.
A 19‐year multi‐centre retrospective review of Meckel's diverticulum, with a focus on laparoscopic stapled diverticulectomy and its safety.
Ringing activity in the Eastern Cape province, South Africa, spanned 30 years, with three sites active concurrently over a 14-year period, and three sites over a 6-year period. In total, in the ...course of 714 ringing days, in all months, we handled 1 207 Amethyst Sunbirds, 708 Southern Double-collared Sunbirds, 707 Greater Double-collared Sunbirds, 381 Grey Sunbirds, 121 Malachite Sunbirds and 140 Collared Sunbirds. Although individuals of all six species were recaptured more than five years after ringing, and despite evidence of the seasonal passage of sunbirds at two sites near the Indian Ocean coast, no birds were recaptured away from the original ringing site. The extent of seasonal movement by these species remains unclear. All species have a complete post-breeding moult, with a period of eclipse plumage in males of the Malachite Sunbird and Southern Double-collared Sunbird. Primary wing-moult in adult Greater and Southern Double-collared Sunbirds extends over three months beginning in December. Inland populations of adult Amethyst Sunbirds and Malachite Sunbirds start primary moult in April. Moult apparently proceeds more rapidly in Malachite Sunbirds (70 days to completion) than in Amethyst Sunbirds (125 days), but the Malachite Sunbird is the only species that frequently displays interrupted/suspended moult in this region. Adult Amethyst Sunbirds in the coastal population evidently start moulting earlier, in late February, with a similar duration to completion as inland birds. Juvenile Amethyst Sunbirds start to moult some two months later than adults in each region and they may complete moult more quickly. Collared Sunbirds appear to have the most protracted moult, extending over five months from November, but estimates of moult parameters for this species and the Grey Sunbird (three months from December) are based on small samples.
Purpose
Granular cell tumours (GCTs) of the pancreas are mostly benign and exceptionally rare, with no unique identifying radiological features. Following a case discussion of a patient with GCT, a ...comprehensive review of available literature was conducted to identify the common diagnostic features associated with GCT.
Methods
Following a case report identified in our institution, a systematic review was conducted by two authors in accordance with Preferred Reporting Items for Systematic review and Meta-Analysis protocols (PRISMA) guidelines. Databases MEDLINE, EMBASE, Scopus, World of Science, and grey literature were searched on August 2021. Inclusion criteria were histopathology diagnosed granular cell tumour of the pancreas.
Results
A 37-year-old male presented with 1 month of abdominal pain and an MRI demonstrating a dilated main pancreatic duct, distal parenchymal atrophy, but no focal lesion. Repeat MRI at 6 months re-demonstrated similar findings and subsequent endoscopic ultrasound was suspicious for main duct IPMN. Following multidisciplinary team discussion, a spleen-preserving distal pancreatectomy was performed. Histopathology demonstrated granular cell tumour with cells diffusely positive for S100 and no malignant transformation.
11 case reports were identified in the literature with diagnosis confirmed on tissue histopathology based on positive immunohistochemical staining for S-100 protein. Eight patients presented with gastrointestinal symptoms with abdominal pain the main presenting complaint (50%). 10 patients underwent CT with portal venous contrast and all underwent endoscopic examination. Imaging findings were similar in five studies for EUS which demonstrated a hypoechoic lesion with homogenous appearance. On non-contrast CT GCT was iso-enhancing, and with portal venous contrast demonstrated hypo-enhancement that gradually enhanced on late phases. Pre-operative diagnosis of pancreatic carcinoma was described in six cases based on imaging and biopsy, resulting in progression to surgical resection. Nine patients were managed surgically and no complications identified on follow-up (6–52 months).
Conclusion
The currently proposed management pathway includes EUS with biopsy and CT, and surgical resection recommended due to malignancy risk. Improved sample collection with EUS-FNA and microscopic assessment utilising S-100 immunohistochemistry may improve pre-operative diagnosis. Limitations include rare numbers in reported literature and short follow-up not allowing an assessment of GCT’s natural history and malignancy risk. Additional cases would expand the current dataset of GCTs of the pancreas, so that surgical resection may be avoided in the future.
Determining the migratory status of seabird populations is crucial for addressing conservation concerns. The Roseate Tern Sterna dougallii is considered endangered in South Africa in view of its ...small breeding population and the threats to eggs and chicks. Earlier works based on capture-recapture data suggest that this population adopts a partial migratory strategy. Updated capture-recapture data were combined with new data on moult and stable isotopes of scapular feathers to determine whether subpopulations could be identified in the South African breeding population. Moult data on 404 individuals failed to identify subpopulations, but two groups were identifiable with the stable isotopes: one group of four individuals exhibiting low carbon and nitrogen stable isotope ratios and a second group (comprising the remaining 152 individuals) with significantly higher ratios. The isotope data suggest that birds from the two groups moulted in different areas. Comparisons with published studies showed that the 152 individuals had likely moulted their scapulars in South African waters, but the moulting area for the remaining four individuals could not be ascertained due to the absence of detailed isoscapes in the southern part of the Mozambique Channel. Further work investigating the genetic differentiation between South African and Madagascan Roseate Terns may bring new insight into the migratory behaviour of the South African population.
Trans‐equatorial avian migrants tend to breed, moult and migrate – the main energy‐requiring events in their lifecycle – at different times. Little is known about the relationship between wing moult ...and pre‐migratory fuelling in waders on their non‐breeding grounds, where time is less constrained than during their brief high‐latitude breeding season. We determined age‐related strategies of Wood Sandpipers Tringa glareola to balance the energetic demands of primary moult against pre‐migratory fuelling in southern Africa by analysing body mass and primary moult at first capture of 1721 birds mist‐netted in 1972–96 at waterbodies in Zimbabwe. Adults moulted all their primaries in August–December, but immatures underwent a supplemental moult of varying numbers of outer primaries in December–April, close to departure. We used locally weighted linear regression to estimate trends in Wood Sandpiper body mass from 1 July to 1 May. They maintained low mass from arrival in July–September to February–early March. Adults fuelled from 10 February to 1 May at a mean rate of 0.25 g/day (sd = 0.16). Most adults (98%) began fuelling 10–75 days after completing primary moult. Immatures fuelled from 4 March to 13 April at 0.24 g/day (sd = 0.14). They used varying strategies depending on their condition: a brief gap between moult and fuelling; an overlap of these processes near departure, leading to slower fuelling; or skipping fuelling altogether and staying in southern Africa for a ‘gap year’. Immatures moulting three or five outer primaries fuelled more slowly than post‐moult birds. Immatures moulting four outer primaries started fuelling 3 weeks later but at a higher rate than did post‐moult birds of this group. In post‐moult immatures, the later they ended moult, the later and faster they fuelled. The heaviest adults and immatures using all moult patterns accumulated fuel loads of c. 50% of lean body mass, and could potentially cross 2397–4490 km to reach the Great Rift Valley in one non‐stop flight. Immatures were more flexible in the timing and extent of moult and in the timing and rate of fuelling than adults. This flexibility enables inexperienced Wood Sandpipers to cope with inter‐annual differences in feeding conditions at Africa's ephemeral inland waterbodies.
Greenshanks Tringa nebularia show various patterns of primary moult in the northern hemisphere, but farther south moult patterns are known only fragmentarily. We Identified geographical patterns in ...primary moult and pre-migratory fattening of Greenshanks on their southernmost African non-breeding grounds. We compared primary moult (using Underhill-Zucchini models) and body mass at a population level based on 356 Greenshanks caught in 1968–1998 at inland wetlands in Zimbabwe, and on the east and west coasts of South Africa. About 20% of immatures replaced one to five outer primaries in December—May, a rare pattern in the north. Sub-adults moulted all primaries on average 40 days earlier than adults, yet at the same rate. Adults started primary moult on average 16–19 days earlier in Zimbabwe and at the east coast than at the west coast (7, 4, 23 September, resp.). These dates correspond with the Greenshanks' broad-front arrival in Zimbabwe and the east coast, and their later arrival at the west coast. Moult took 10–17 days longer on average in Zimbabwe and at the east coast than at the west coast (122, 115, 105 days, resp.), thus the end of moult coincided within six days (31 December—6 January). Pre-migratory fattening began about 13–19 January across all regions. The mean departure fat loads of adults were 76 g In Zimbabwe, 116 g at the west coast and 125 g at the east coast. The heaviest adults from all three regions could reach the Nile Valley or the Red Sea coast in one non-stop flight. We suggest that Greenshanks at inland wetlands of Zimbabwe benefit from a shorter return migration distance and lower competition than at the coasts, and abundant food during the entire austral summer In favourable years, but can move on to the coasts if conditions deteriorate.
Five to seven subspecies of Antarctic Tern (Sterna vittata) are recognised, with at least three (S. v. vittata, S. v. tristanensis and S. v. sanctipauli) wintering in South Africa. Morphological ...characters used to define these subspecies are not perfectly reliable, but fidelity to nesting site suggests they could be genetically distinct. We used morphological data and DNA to investigate the validity of subspecies. We further used stable isotope analysis of feather samples collected from the non-breeding grounds in South Africa to attempt to ascertain the population of origin. Nuclear and mitochondrial DNA sequence data identified two major genetic clades: one mostly comprised individuals partially or completely matching the morphological description of S. v. tristanensis, the other included individuals from S. v. vittata and S. v. sanctipauli. Stable isotope values indicated that juveniles originated from at least three populations. Irrespective of their morphological and genetic characteristics, most immatures moulted in Antarctic waters, and adults moulted in various habitats. Their colony of origin could not therefore be inferred from stable isotope values from feathers. Results indicate that morphological groupings may reflect a north–south cline across the Indian Ocean. Adequate conservation strategies require rigorous reassessment of the currently accepted subspecies, including DNA analyses of samples from the breeding grounds, particularly on Amsterdam and St Paul Islands.
The Eastern Cape population of the Damara Tern Sternula balaenarum was estimated to be 25–29 pairs in the 2008/09 and 2009/10 breeding seasons. The population appears to be stable and has probably ...increased slightly since the early 1990s. An eastward shift of the majority of nest sites in the Alexandria dunefields of 5–10 km was recorded since the early 1990s. Breeding Damara Terns caught at night and colour-flagged in the Alexandria dunefields averaged 12% heavier than the average mass of birds handled in Namibia and egg masses ranged from 11% to 22% heavier than 21 fresh egg masses recorded in Namibia. Adult Damara Terns caught at night while incubating, were ringed and marked with coloured leg-flags. All chicks located were also ringed and leg-flagged. A stable isotope analysis of scapular feathers suggested that breeding adults from the Eastern Cape may moult in similar areas to the Namibian population, i.e. West Africa. Small numbers of Damara Terns were recorded during the winter in the Eastern Cape. Although these included no colour-flagged birds, the numbers of birds marked were probably too low to draw any definite conclusions regarding the origin of over-wintering Damara Terns.
Immature migrant waders have more complex patterns of primary moult than adults, but these have been described only fragmentarily. The Wood Sandpiper Tringa glareola breeds in the taiga region of the ...Palearctic and part of the population migrates to southern Africa. We selected this population for a study of the primary moult strategies of an immature wader. After analysing the moult formulae of 674 immatures, we discuss potential factors that influence the choice of moult strategy. All moulters replaced two to six outer primaries; 91% moulted four or five. We used the Underhill-Zucchini model to estimate the timing and duration of moult in immatures replacing different numbers of primaries. A slow moult of five or six primaries, adopted by 29%, lasted on average 98-111 days, beginning on average 8-16 December. Moult of four primaries (63%) began on 6 January and averaged 73 days. A rapid moult of three primaries (7%) began on 24 January and averaged 55 days. All groups ended their moult between 19 and 28 March. GLM models showed that heavier immatures were more likely to start moulting than leaner birds. This tendency was more pronounced in November-January than in later months. The later the moult started, the fewer feathers were replaced and the faster the process. Departure time set the limit for the end of moult. We suggest the ability to choose different strategies allows immature Wood Sandpipers to adjust their moult to the variable conditions they encounter at wetlands in southern Africa.
