Acute/relapsing experimental autoimmune encephalomyelitis: Induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE-induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy.

The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors

“…Spontaneous immune conditions in mice can be transferred by hemopoietic stem cells, which differentiate into T and B lymphocytes before the disease is manifest, leading to the hypothesis that the cause of immune diseases may lie in the hemopoietic stem cells, and that syngeneic bone marrow transplantation (in conjunction with an immunosuppressive treatment) induces a state of long-term unresponsiveness to myelin antigens presumably by a mechanism of tolerance that is antigen specific (9)(10)(11)(12)(13)(14). Among bone marrow cells, CD34 ϩ cells may be responsible for this effect directly or through their progeny, as exemplified by MS patients who received autologous CD34 ϩ cells (15).…”

Stem Cell-based Therapies in Multiple Sclerosis

“…In addition, the interesting possibility was raised that the replacement of the aberrant immune system by a pristine, expectantly non-autoreactive system, generated by the hemopoietic stem cell graft, may possibly restore selftolerance [9].…”

T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants

“…For example, experiments using this approach in murine multiple sclerosis (MS) showed control of the disease after SCT. 1,2 Earlier clinical studies indicated that long-term remissions of several autoimmune diseases could be achieved after SCT. [3][4][5] Here, we applied extensive ex vivo and in vivo T-cell depletion in combination with autologous SCT as salvage treatment for MS. Ex vivo T-cell depletion was done by preparing autografts enriched for CD34 þ hematopoietic stem cells, while in vivo T-cell depletion was accomplished by administration of antithymocyte globuline (ATG) and total body irradiation (TBI).…”