Cotransplantation of mesenchymal cells and a higher relapse rate: a role for HLA-G molecules?

This is a Letter to the Editor to comment the paper by Ning et al (1) reporting a correlation between the cotransplantation of mesenchimal stem cells (MSCs) in allogeneic haemapoietic stem cell transplantation and a higher recurrence rate of malignant haematologic diseases. The authors concluded their paper suggesting that “the use of MSCs must be handled with extreme caution before a large-scale trials is performed”. Recently, several studies have reported the ability of MSCs, when co-cultured with activate peripheral blood mononuclear cells (PBMC) or directly activated by exogenous Interleukin 10, to modulate membrane bound and soluble HLA-G antigens (2-4). HLA-G antigens are non classical HLA-class I molecules characterized by tolerogenic and anti-inflammatory functions. In particular, both membrane and soluble HLA-G molecules have demonstrated to inhibit Natural killer (NK) and CD8+ T cell mediated cytolysis, CD4+ T lymphocyte proliferation and dendritic cell maturation. Moreover the expression of HLA-G antigens has been associated to the induction of regulatory T cells (4). Overall it is currently accepted that HLA-G molecules, by direct and indirect mechanisms, can inhibit innate and adaptative immune response. The production of sHLA-G molecules by MSCs (2-4) has suggested, in addition to other mechanisms, a rationale for the immunomodulatory properties of MSCs in preventing graft versus host disease (GVHD). Several researches have demonstrated that HLA-G modulation represents a beneficial event in organ transplantations, autoimmune diseases and pregnancy where the down-regulation of the immune response is essential for a positive outcome. On the opposite, the presence of HLA-G antigens has been associated to clinical negative consequences in cancer and viral infections where the tolerogenic function of these molecules permits to the mutated / infected cells to avoid the innate and adaptative immune response. In particular the HLA-G expression by cancer tissues and the relationship between plasma sHLA-G levels and cancer development (5-8) confirm the role of HLA-G molecules in sustaining the immune escape of cancer cells. The association between MSCs cotransplantation and malignant haematologic diseases development reported by Ning et al. (1) could be related to the functional ability of HLA-G molecules on one side to counteract GVHD but on the other side to permit the relapse of the disease. This hypothesis underlines the necessity of further studies to analyze plasma sHLA-G concentrations in MSCs cotransplanted patients in a longitudinal follow-up. The detection of a significant correlation between sHLA-G concentrations, GVHD prevention and relapse rate could identify a possible cut off in sHLA-G plasma levels responsible for the occurrence of these two phenomena

Comment on “Experimental Extracorporeal Photopheresis Inhibits the Sensitization and Effector Phases of Contact Hypersensitivity via Two Mechanisms: Generation of IL-10 and Induction of Regulatory T Cells”.

Letter to the Editor on the paper by paper by Maeda and coauthors (Experimental Extracorporeal Photopheresis Inhibits the Sensitization and Effector Phases of Contact Hypersensitivity via Two Mechanisms: Generation of IL-10 and Induction of Regulatory T Cells. J Immunol 2008; 181:5956-5962

A novel mutation of HFE explains the classical phenotype of hereditary hemochromatosis in a C282Y carrier

Hereditary hemochromatosis (HH) is the most autosomal recessive disorder in Caucasians, affecting approximately 1 in 300 person. It is characterized by iron overload in many organs, leading to cirrhosis, hepatocellular carcinoma, diabetes, arthritis, heart failure and hypogonadism. Most of HH patients are homozygous for the C282Y mutations. Some C282Y-carrier patients have been identified to be compound heterozygous for other mutations (H63D, S65C, G93R, IVS3+1G>T, 203delT). We report a patient with classical HH who is compound heterozygous for C282Y and a novel missense mutation in the exon 4. This is a 848A>C mutation that causes glutamine to proline substitution at position 283 (Q283P). We hypothesize that the Q283P variant may disrupt the beta2-microglobulin binding site in the HFE protein

Potential role of soluble HLA-G molecules in multiple sclerosis

Nonclassical human leukocyte antigen (HLA)-G antigens in soluble form (sHLA-G) have recently been suggested to have a potential role as immunomodulatory factors in multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system of unknown etiology and supposed autoimmune origin. sHLA-G levels were elevated in the cerebrospinal fluid (CSF) of MS patients who were intrathecally synthesized, predominantly represented by the HLA-G5 isoform and even more elevated in cases of inactive disease, as determined by magnetic resonance imaging. In MS, CSF sHLA-G concentrations were also related to the formation of an intrathecal anti-inflammatory microenvironment based on a positive correlated to CSF interleukin-10 titers and an inverse association to the levels of antiapoptotic sFas molecules in the CSF. Expression of HLA-G antigens was detected in microglia, macrophages, and endothelial cells within and around MS lesions and was enhanced in microglial cells by T-helper-1 proinflammatory cytokines. A novel subpopulation of naturally occurring CD4(+) and CD8(+) regulatory T cells expressing HLA-G1 and secreting HLA-G5 was identified in the CSF of MS patients. Taken together, these findings seem to indicate that sHLA-G antigens may be implicated in the termination of MS autoimmunity and associated with remission of the disease through their function as anti-inflammatory molecules. However, the mechanisms operating in the immunomodulatory circuit mediated by sHLA-G proteins remain to be clarified

Responses to extracellular ATP of lymphoblastoid cell lines from Duchenne muscular dystrophy patients

We have observed a striking difference in the response to extracellular ATP in lymphoblastoid cell lines established from Duchenne muscular dystrophy patients and normal subjects. Duchenne muscular dystrophy cells stimulated by extracellular ATP underwent a large increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) and plasma membrane depolarization, while normal cell lines were little or not at all responsive. These changes in intracellular ion homeostasis were due to activation of an ATP-gated membrane channel permeable to Na+ and Ca2+, with little or no contribution of Ca2+ release from intracellular stores. The channel was selectively activated by ATP, since other purine/pyrimidine nucleotides were ineffective, and it was inhibited by pretreatment with oxidized ATP, a compound previously reported to irreversibly inhibit P2 purinergic receptors. In the presence of extracellular ATP, lymphoblastoid cells established from Duchenne muscular dystrophy patients, but not from healthy controls, underwent rounding and swelling and eventually lysed. The results of this study suggest that lymphoblastoid cells isolated from Duchenne muscular dystrophy patients are eminently sensitive to stimulation by extracellular ATP

Association of CYP1B1 with hypersensitivity induced by Taxane therapy in breast cancer patients.

Purpose: Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in Taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (SNPs) in these three genes and the occurrence of Taxane-induced toxicity. Methods: We studied 95 patients affected by breast cancer and under treatment with Taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for single nucleotide polymorphisms in the CYP2C8 (alleles *1, *2 *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by Real-Time PCR assay. Results: We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to Taxane treatment. Conclusions: We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-Taxane adduct and possibly inhibit Taxane toxicity. We suggest that CYP1B1 might affect Taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker