Role of Non-Major Histocompatibility Complex Antigens in the Rejection of Transplanted Myoblasts1

Abstract

Myoblasts obtained from donors histoincompatible for several non-major histocompatibility complex antigens (i.e., including minor histocompatibility antigens) and from syngeneic donors were transplanted without any immunosuppression into the muscles of male dystrophic C57BL/10J mdx/mdx mice. Myoblasts from syngeneic mice resulted in the formation of a high percentage of dystrophin-positive fibers 16 weeks after the transplantation. There was no evidence of a cellular immune reaction against the donor myoblasts, i.e., no infiltration by CD4 or CD8 lymphocytes and no increased expression of granzyme B and interferon-gamma mRNAs. Transplantation of myoblasts obtained from donors histoincompatible only for non- major histocompatibility complex antigens produced a transient increase of dystrophin-positive fibers at 4 weeks after transplantation for some donor strains but not for others. For donor strains that did produce an increase at 4 weeks, the number of dystrophin-positive fibers was reduced 16 weeks after the transplantation. There was evidence of a cellular immune reaction-infiltration by CD4 and by CD8 lymphocytes and increased expression of granzyme B and interferon-gamma mRNAs. Transplantation of myoblasts obtained from male C57BL/10J +/+ mice into female C57BL/10J mdx/mdx mice also led to the presence of only a few dystrophin-positive fibers with the same signs of cellular immune reaction. In this later case, the cellular immune response was attributed to the H-Y minor antigens. Finally, antibodies against fetal calf serum were detected after both syngeneic and nonsyngeneic transplantations, indicating that the culture medium may also be a source of antigens. In mice, the presence of these antibodies against culture medium did not reduce the success of a first syngeneic transplantation.

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…It was even suggested that this lymphocytic attack not only rejects the hybrid myofibers resulting from the cell transplantation, but also can damage the host myofibers by the "bystander" effect of released cytokines [176]. Incompatibility in minor antigens can also trigger acute rejection of hybrid myofibers, as observed in mice after syngeneic transplantation into females of myoblasts obtained from males [179].…”

Problems and solutions in myoblast transfer therapy

“…Non dystrophin-based alternatives to MTT are designed to avoid this immune problem (see Alternatives and novel approaches below). Interestingly, not only can antibodies to dystrophin be a problem, but host antibodies specific for fetal calf serum, a reagent used in the culture of myoblasts, have been detected in blood samples of mice soon after MTT [32], implicating a long-term detrimental effect of the tissue culture process. This point is addressed further in the following section.…”

Real-time monitoring of cell transplantation in mouse dystrophic muscles by a secreted alkaline phosphatase reporter gene

“…A quantitative method to analyze MPC survival is a quantitative PCR measurement of Y chromosome expression by the male donor MPC transplanted in the female muscle. 11 Besides being technically not easy and of limited accuracy, this method suffers from an inherited disadvantage of the development of immune response in the female host against the male minor histocompatibility HY antigen expressed in donor cells, as was shown by Boulanger et al 12 The use of mSeAP as a reporter gene presents several advantages. First, the lack of an immune response against mSeAP (unlike lacZ, Luciferase and the Y-chromosome).…”