New strategies for allogeneic BMT

Abstract

Summary:In humans, the success rate of BMT across major histocompatibility complex (MHC) barriers is lowered by graft-versus-host disease (GvHD), graft rejection and incomplete T-cell recovery. To prevent GvHD, we attempted to minimize the contamination of bone marrow cells (BMCs) with T cells from the peripheral blood when donor BMCs were collected, finally establishing a new 'Perfusion Method' using cynomolgus monkeys. There was significantly less contamination of BMCs with T cells in this method (o6%) than in the conventional 'Aspiration Method' (420%) consisting of multiple aspirations of BMCs from the iliac crest. Using radio-sensitive and chimerism-resistant MRL/lpr mice, we also established a new method for allogeneic (allo) BMT and organ allografts. In this method, whole BMCs, containing a small number of T cells and mesenchymal stem cells (MSCs), were directly injected into the bone marrow cavity (intrabone marrow [IBM]-BMT). MRL/lpr mice treated with IBM-BMT survived more than 2 years without showing the symptoms of autoimmune diseases. IBM-BMT thus has several advantages: (i) no GvHD develops even if T cells are not depleted from BMCs; (ii) no graft failure occurs even if the dose of radiation as the conditioning regimen for allo BMT is reduced to 5Gy  2; (iii) hemopoietic recovery is rapid; and (iv) the restoration of T-cell functions is quick and complete even in donorrecipient combinations across MHC barriers. We believe that these strategies for allo BMT and organ allografts herald a new era in transplantation, and that they would be helpful in allogeneic HSCT of autoimmune diseases.

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

“…One potential limitation of the experimental design is the challenge in generating complete chimerism. This is particularly difficult in MRL/lpr mice, as they are systemically radiosensitive although hematopoietically radioresistant [ 55 ]. Nevertheless, the split-dose BMT method utilized herein has previously been shown to generate over 95 % engraftment [ 56 ].…”

Polarization of T Lymphocytes Is Regulated by Mesenchymal Stem Cells in NZBWF1 and BALB/c Mice

“…The results imply that lupus MSCs might be defective, but whether these defects are pathogenic to the disease remains to be explored. Normal MSCs made T-subset a shift to Th1, which might lead to an improvement of the illness and may offer one explanation for the clinical outcome observed by other authors [ 11 ]. So we hypothesize that MSCs would influence the maturation and differation of T cells and hence the Th polarization of an immune response in vivo.…”

“…In addition, in vitro culture-expanded autologous MSCs could be infused intravenously without toxicity [ 10 ]. It was reported that co-transplantation of MSCs along with HSCs was prior to simple HSCs transplantation in MRL/lpr mice [ 11 ].…”