Immunological Mechanisms of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell
      transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis
      (MS).

      The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell
      mediated immune destruction of myelin is thought to be an important element. We hypothesize,
      and the results of previous studies suggest, that radical immuno-ablation characterized by a
      profound T cell depletion can arrest the progression of disease. Patients with MS with poor
      prognosis based on the rate of progression and refractoriness to approved treatments
      (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the
      collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune
      ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with
      autologous peripheral blood stem cells, a procedure similar to autologous bone marrow
      transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the
      overall treatment-related mortality worldwide is approximately 10%, the collaborating
      institution and investigators have an outstanding safety record in performing the procedure
      with no fatal adverse events after having transplanted more than 30 transplants with a
      previously more aggressive regimen than the one that is in use now. The underlying rationale
      for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in
      disease-susceptible individuals, may have been activated by previous exposure to
      environmental agents or other acquired mechanisms of immune dysregulation.

      In the proposed study we plan to address whether HSCT or immunoablation without stem cell
      rescue act beneficially in MS via the eradication of myelin-reactive T cells and
      reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we
      will compare peripheral blood T cell reactivities to myelin antigens before and after the
      treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells
      that do not recognize these myelin antigens, we will search for clonally expanded cells in
      the blood of MS patients before treatment employing molecular analysis of T cell receptor
      repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of
      patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates
      with disease remission, we will attempt to isolate these cells in culture from pre-treatment
      samples and determine their specificity using combinatorial peptide libraries. We would use
      the same approach in case of reappearance or new clonal expansions concomitant to disease
      relapses. We will combine these studies with a broader, unbiased approach that employs
      microarray technology to identify potential changes in gene expression profiles. This
      approach may also lead to the identification of novel therapeutic targets for pharmacological
      treatment.
    

Detailed description: 
      Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell
      transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis
      (MS).

      The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell
      mediated immune destruction of myelin is thought to be an important element. We hypothesize,
      and the results of previous studies suggest, that radical immuno-ablation characterized by a
      profound T cell depletion can arrest the progression of disease. Patients with MS with poor
      prognosis based on the rate of progression and refractoriness to approved treatments
      (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the
      collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune
      ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with
      autologous peripheral blood stem cells, a procedure similar to autologous bone marrow
      transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the
      overall treatment-related mortality worldwide is approximately 10%, the collaborating
      institution and investigators have an outstanding safety record in performing the procedure
      with no fatal adverse events after having transplanted more than 30 transplants with a
      previously more aggressive regimen than the one that is in use now. The underlying rationale
      for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in
      disease-susceptible individuals, may have been activated by previous exposure to
      environmental agents or other acquired mechanisms of immune dysregulation.

      In the proposed study we plan to address whether HSCT or immunoablation without stem cell
      rescue act beneficially in MS via the eradication of myelin-reactive T cells and
      reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we
      will compare peripheral blood T cell reactivities to myelin antigens before and after the
      treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells
      that do not recognize these myelin antigens, we will search for clonally expanded cells in
      the blood of MS patients before treatment employing molecular analysis of T cell receptor
      repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of
      patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates
      with disease remission, we will attempt to isolate these cells in culture from pre-treatment
      samples and determine their specificity using combinatorial peptide libraries. We would use
      the same approach in case of reappearance or new clonal expansions concomitant to disease
      relapses. We will combine these studies with a broader, unbiased approach that employs
      microarray technology to identify potential changes in gene expression profiles. This
      approach may also lead to the identification of novel therapeutic targets for pharmacological
      treatment.
    

Intervention name(s): Stem Cell Transplanataion
Intervention type(s): Procedure
Primary purpose: Treatment
Keywords: Demyelination; Inflammation; Immunosuppression; Autoimmunity; Bone Marrow; Multiple Sclerosis