Grégoire Wieers

A Galectin-3 Ligand Corrects the Impaired Function of Human CD4 and CD8 Tumor-Infiltrating Lymphocytes and Favors Tumor Rejection in Mice

Human CD8(+) tumor-infiltrating T lymphocytes (TIL), in contrast with CD8(+) blood cells, show impaired IFN-γ secretion on ex vivo restimulation. We have attributed the impaired IFN-γ secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N-acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8(+) TIL treated with an anti-galectin-3 antibody had an increased IFN-γ secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8(+) TIL but also CD4(+) TIL treated with GCS-100 secreted more IFN-γ on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone.

Early immunological monitoring after pediatric liver transplantation: cytokine immune deviation and graft acceptance in 40 recipients.

Cytokine deviation may be a factor contributing to graft acceptance. We analyze, in the context of liver transplantation, circulating cytokine levels and their mRNA precursors in liver biopsy samples to study a putative correlation with early immunologic outcome. Forty primary pediatric liver recipients were submitted to a prospective immune monitoring protocol, including 8 of 40 patients with an early, biopsy‐proven acute rejection episode. The 32 patients with graft acceptance showed markedly increased interleukin (IL)‐10 blood levels at 2 hours after reperfusion on days 1 and 4 after transplantation as compared with baseline, whereas patients with graft rejection only exhibited increased IL‐10 levels at 2 hours. A good correlation was observed between IL‐10 peripheral levels and levels ascertained by IL‐10 reverse transcriptase–polymerase chain reaction at 2 hours and on day 7. Patients with graft acceptance also showed a decrease in interferon gamma (IFN‐γ) at 1 and 2 hours after reperfusion on days 1, 4, 7, 14, and 28 after transplantation. One patient with graft tolerance who had subsequent immunosuppression withdrawal after posttransplantation lymphoproliferative disease showed a similar intraoperative IL‐10 pattern, whereas posttransplantation tumor necrosis factor alpha and IFN‐γ levels greatly decreased. The occurrence of cytokine immune deviation may therefore be related to early graft acceptance in children who receive liver transplants. Liver Transpl 13:426–433, 2007.

Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why?

Tumor-infiltrating T lymphocytes (TILs) are observed in a number of human primary or metastatic tumors. Recently, gene expression profiling experiments suggested that the presence of T cells in metastatic melanomas before vaccinating the patients with tumor antigens could be a biomarker for clinical benefit from the vaccines. In this context, we review results pertaining to TILs in human melanomas, their prognostic value, and some possible reasons why their presence could help in selecting melanoma patients for vaccination against tumor-specific antigens.

The immunological monitoring of alloreactive responses in liver transplant recipients: a review.

The aim of this work is to review the current knowledge in the field of immunological monitoring of allogenic responsiveness in clinical liver transplantation. When compared to other solid‐organ transplants, liver allografts are considered as immunologically privileged, and, accordingly, constitute a favorable setting to develop experimental as well as clinical strategies for minimization of immunosuppression and even induction of operational tolerance. The validation of simple, reliable, noninvasive assays exploring antidonor alloreactivity will constitute a crucial step toward implementing such approaches in the clinic. In contrast to research in rodents claiming the development of donor‐specific tolerance in case of graft survivals of over 100 days without immunosuppression, it is impractical to confirm tolerance induction in this way in humans. Promising candidate assays include the detection of post‐transplant immune deviation, of circulating precursors of dendritic cells subtypes, and of regulatory T cells. A conceptual framework for the development of tolerance assays in clinical liver transplantation is also proposed. Liver Transpl 12:373–383, 2006.

The immunological monitoring of kidney and liver transplants in adult and pediatric recipients

Over the last half century, kidney and liver transplantation have been recognized as the treatment of choice for adult and children with end-stage renal or liver failure. Infants present a relative naïve immune system, but they are capable of mounting both cellular and humoral immune responses to the foreign antigens presented by the allograft. Immune monitoring is a way of measuring functional and molecular correlates of immune reactivity which may provide clinically useful information for identifying patients who have an increase risk of acute rejection prior to clinical symptoms or develop transplant tolerance. However, although numerous assays have been shown to predict rejection, to date no assays have been demonstrated to detect or predict transplantation tolerance. This is a summary of the published literature on promising antigen-specific and non-antigen-specific assays used for immunological monitoring in solid organ transplantation. This work also attempts to review their applicability to pediatric transplantation, specifically, pediatric kidney and liver recipients.

Immune Suppression in Tumors as a Surmountable Obstacle to Clinical Efficacy of Cancer Vaccines

Human tumors are usually not spontaneously eliminated by the immune system and therapeutic vaccination of cancer patients with defined antigens is followed by tumor regressions only in a small minority of the patients. The poor vaccination effectiveness could be explained by an immunosuppressive tumor microenvironment. Because T cells that infiltrate tumor metastases have an impaired ability to lyse target cells or to secrete cytokine, many researchers are trying to decipher the underlying immunosuppressive mechanisms. We will review these here, in particular those considered as potential therapeutic targets. A special attention will be given to galectins, a family of carbohydrate binding proteins. These lectins have often been implicated in inflammation and cancer and may be useful targets for the development of new anti-cancer therapies.

Pre- and post-transplant monitoring of granzyme B enzyme-linked immunosorbent spot assay in pediatric liver recipients

UNLABELLED This study aims to investigate potential role of granzyme B enzyme-linked immunosorbent spot (GrB ELISPOT) for immunological monitoring in pediatric liver transplantation. PATIENTS AND METHODS Peripheral blood mononuclear cells from 28 pediatric recipients were serially tested for GrB-producing donor-reactive cells at day 0 pre-transplantation (baseline) and days 7, 14, and 28 post-transplantation. RESULTS At baseline, no difference of GrB value was found in acute rejection (14/28) compared to normal graft function patients (day 0: 4(3.9) spots versus 5(2.9) spots, respectively: p=0.65). At day 7 post-transplantation, acute rejection patients showed frequencies of GrB ELISPOT higher than those with normal graft function, but the differences observed were not statistically significant (day 7: 15(4.9) spots versus 10(4.0) spots, respectively: p=0.55). GrB increased significantly at day 7 from baseline in the rejection group (15(4.9) spots versus 4(3.9), respectively p=0.04), whereas corresponding changes were not significant in the group without rejection (10(4.0) versus 5(2.9), respectively: p=0.15). CONCLUSION GrB ELISPOT pre-transplantation could not predict the occurrence of early post-transplant acute rejection; similarly frequencies at days 7, 14 and 28 could not be correlated with acute rejection in pediatric liver recipients. However, a kinetic study of GrB ELISPOT could be helpful to predict or confirm early rejection in the small group of liver allograft recipients analyzed in this study.

Spinal and sacroiliac gouty arthritis: report of a case and review of the literature

In this case report, we describe an “uncommon” case of axial gouty arthropathy in a 69-year-old woman with bilateral sciatica that was thoroughly evaluated with conventional radiography, CT scan, magnetic resonance imaging, bone scintigraphy, and PET-CT. Axial gouty arthropathy should be included in the differential diagnosis of chronic low back pain, mainly when several risk factors for gout are present.

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Chyloma: an uncommon cause of supraclavicular swelling.

Abstract We report the case of a 46-year-old woman who noticed a swelling of the left supraclavicular fossa of rapid onset soon after a Mycoplasma Pneumoniae upper respiratory infection. On the basis of clinical history, physical examination and imaging findings, a diagnosis of chyloma due to intense non-productive coughing bouts was made. The supraclavicular swelling progressively disappeared after a few days. This observation prompted us to briefly review the pathophysiology of chylomas.