It is becoming increasingly evident that selecting an optimal source of mesenchymal stromal cells (MSCs) is crucial for the successful outcome of MSC-based therapies. During the search for cells with potent regenerative properties, Sertoli cells (SCs) have been proven to modulate immune response in both in vitro and in vivo models. Based on morphological properties and expression of surface markers, it has been suggested that SCs could be a kind of MSCs, however, this hypothesis has not been fully confirmed. Therefore, we compared several parameters of MSCs and SCs, with the aim to evaluate the therapeutic potential of SCs in regenerative medicine. We showed that SCs successfully underwent osteogenic, chondrogenic and adipogenic differentiation and determined the expression profile of canonical MSC markers on the SC surface. Besides, SCs rescued T helper (Th) cells from undergoing apoptosis, promoted the anti-inflammatory phenotype of these cells, but did not regulate Th cell proliferation. MSCs impaired the Th17-mediated response; on the other hand, SCs suppressed the inflammatory polarisation in general. SCs induced M2 macrophage polarisation more effectively than MSCs. For the first time, we demonstrated here the ability of SCs to transfer mitochondria to immune cells. Our results indicate that SCs are a type of MSCs and modulate the reactivity of the immune system. Therefore, we suggest that SCs are promising candidates for application in regenerative medicine due to their anti-inflammatory and protective effects, especially in the therapies for diseases associated with testicular tissue inflammation.

• Keywords
• Mesenchymal stem cells. Sertoli cells. Immunomodulation. Mitochondrial transfer,
• MeSH
• Anti-Inflammatory Agents MeSH
• Immunity MeSH
• Humans MeSH
• Mesenchymal Stem Cells * MeSH
• Mitochondria MeSH
• Sertoli Cells * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH

In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin (IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase (iNOS), arginase, heme oxygenase-1 (HO-1) or indoleamine-2,3-dioxygenase (IDO), the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as iNOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules (NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.

• Keywords
• Arginase, Graft rejection, Immunoregulation, Macrophages, Nitric oxide, Th1/Th2 balance, Tolerance,
• Publication type
• Journal Article MeSH

AIM: To determine the effectiveness of treatment with immunosuppressive drugs and monoclonal antibodies (mAb) after penetrating keratoplasty in two different models of high risk mouse recipients. METHODS: Corneas were grafted orthotopically in mouse models of high risk recipients with either neovascularisation of the graft bed or presensitisation to graft donor antigens. Recipients were treated with mAb against CD4(+) or CD8(+) cells or against T cells, or were treated with cyclosporin A (CsA) or mycophenolate mofetil (MMF), or a combination of both drugs. RESULTS: Control untreated recipients with neovascularised graft bed or presensitised to the graft donor antigens rejected corneal allografts in 12.5 (SD 2.3) and 9.9 (1.6) days, respectively. Treatment of graft recipients with a neovascularised graft bed with mAb anti-CD4 or anti-T cells, but not with mAb anti-CD8 or with immunosuppressive drugs, resulted in a significant prolongation of graft survival; 75% and 28.5%, respectively, of grafts survived for more than 45 days after grafting. However, none of the treatments were successful in presensitised recipients. CONCLUSIONS: Treatment of high risk recipients with mAb anti-CD4 is more effective in preventing corneal allograft rejection than the treatment with mAb anti-CD8 or the immunosuppressive drugs MMF and CsA. However, the effectiveness of the treatment depends on the recipients' pretransplantation risk type.

• MeSH
• CD4-Positive T-Lymphocytes immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Cyclosporine therapeutic use   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Immunosuppression Therapy methods   MeSH
• Keratoplasty, Penetrating * MeSH
• Mycophenolic Acid analogs & derivatives   therapeutic use   MeSH
• Disease Models, Animal MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Postoperative Care methods   MeSH
• Graft Survival drug effects   immunology   MeSH
• Graft Rejection immunology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cyclosporine MeSH
• Immunosuppressive Agents MeSH
• Mycophenolic Acid MeSH
• Antibodies, Monoclonal MeSH

Heroin treatment or abusive drug addiction influences many physiological functions, including the reactions of the immune system. Although suppression of various manifestations of the immune system after heroin (or morphine) administration has been reported, we show here that production of proinflammatory cytokines and nitric oxide (NO) was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated recipients. Mice were treated by a subcutaneous administration of heroin (diacetylmorphine) given in one or repeated daily doses. The ability of spleen cells from treated mice to respond in vitro to alloantigens and to produce IL-2, IL-4, IL-10 and IFN-gamma, and the production of IL-1beta, IL-12 and NO by peritoneal macrophages, were tested. Within 2 h after heroin administration, proliferative responses to alloantigens and the production of IL-1beta, IFN-gamma, IL-12 and NO were enhanced significantly. In contrast, the production of anti-inflammatory cytokines IL-4 and IL-10 was at the same time rather decreased. As a consequence, skin allografts in heroin-treated mice were rejected more promptly than in untreated or vehicle-treated recipients. Similarly, the growth of allogeneic tumours induced by high doses of tumour cells was suppressed significantly in heroin-treated mice. The enhancing effects of heroin on the production of proinflammatory cytokines were antagonized by naltrexone, a specific inhibitor of classic opioid receptors. These results show that heroin treatment augments production of proinflammatory cytokines and accelerates allotransplantation reactions. The observations thus illustrate the complexity of the effects of heroin on the immune system and should be taken into account during medical treatment of opiate addicts and in the use of morphine to decrease pain in various clinical situations.

• MeSH
• Cytokines blood   MeSH
• Neoplasms, Experimental drug therapy   immunology   MeSH
• Fibrosarcoma drug therapy   immunology   MeSH
• Heroin pharmacology   MeSH
• Transplantation, Homologous MeSH
• Interferon-gamma biosynthesis   MeSH
• Interleukin-1 biosynthesis   MeSH
• Interleukin-10 biosynthesis   MeSH
• Interleukin-12 biosynthesis   MeSH
• Interleukin-2 biosynthesis   MeSH
• Interleukin-4 biosynthesis   MeSH
• Cells, Cultured MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Naltrexone pharmacology   MeSH
• Narcotic Antagonists pharmacology   MeSH
• Narcotics pharmacology   MeSH
• Nitric Oxide metabolism   MeSH
• Macrophages, Peritoneal metabolism   MeSH
• Spleen immunology   MeSH
• Skin Transplantation immunology   MeSH
• Transplantation Immunology drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cytokines MeSH
• Heroin MeSH
• Interferon-gamma MeSH
• Interleukin-1 MeSH
• Interleukin-10 MeSH
• Interleukin-12 MeSH
• Interleukin-2 MeSH
• Interleukin-4 MeSH
• Naltrexone MeSH
• Narcotic Antagonists MeSH
• Narcotics MeSH
• Nitric Oxide MeSH