MSC-based therapies in solid organ transplantation.

Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169-1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107-111, 2013; Perico et al. in Transpl Int 26:867-878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412-422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.

Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.

Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types.

[The liver as an immunological organ]. / Die Leber als immunologisches Organ.

In many species, liver transplants induce antigen-specific immunological tolerance. Furthermore, the liver seems to play an important role in oral tolerance although the exact mechanisms as to how the liver induces immunological tolerance still need to be defined. Apart from the presence of an unusual subset of effector cells of the innate immune system, the liver is rich in CD 8+ T cells with an activated and preapoptotic phenotype. In this article, we discuss the suggested hypothesis to explain this phenotype. In addition, we discuss the different cell types that have been suggested to serve as antigen-presenting cells (APC) for naïve T cells. Interestingly, different APCs seem to use different mechanisms to induce tolerance while hepatic stellate cells were reported to induce an effective immune response.

[Case report--surgical therapy of a retroperitoneal liposarcoma weighing 45 kg]. / Fallbericht - Chirurgische Therapie eines 45 kg schweren retroperitonealen Liposarkoms.

Due to the late onset of symptoms, retroperitoneal liposarcoma are often diagnosed in advanced stages when adjacent organs have been infiltrated and the tumours have reached extensive sizes. Surgery remains the first choice of therapy. We report on the primary resection of a 45-kg liposarcoma that was removed en-bloc including the left kidney and descending colon with -tumour-free margins. Nine months later, the follow-up revealed a right-sided recurrence of the tumour, which was surgically removed including the right ureter. Since then, the patient has been without any signs of tumour recurrence or metastases. This report demonstrates that even extreme-ly large tumours can be removed safely and that the size is not a contraindication for primary surgical treatment. Local recurrence is common as seen in our case, and occurs even after R0 resection up to 10 years after the first operation. Recurrences should be surgically removed as this is the only treatment which has been shown to increase survival in even R1 and R2 situations.