BMT for Severe Autoimmune Diseases: An Idea Whose Time Has Come

BMT for Severe Autoimmune Diseases: An Idea Whose Time Has Come

ABSTRACT: Most patients with autoimmune diseases are thought to have a a normal life expectancy, and thus are treated conservatively. However, these diseases have a diverse clinical course. A small subset of patients have "severe autoimmune diseases," or SADS, which are rapidly progressive and are associated with early mortality. If patients with SADS can be identified before they develop irreversible organ damage, aggressive intervention would be indicated. Consequently, patients with SADS are now being enrolled in experimental protocols of immune ablation and hematopoietic stem-cell rescue (ie, bone marrow transplantation [BMT]) at several US institutions. For various reasons, including the high cost of BMT, it will probably be years before the benefits, if any, of this procedure are known. [ONCOLOGY 11(7):1001-1017, 1997]


There are numerous autoimmune diseases that, depending on the predominant organ system involved, are treated by a variety of medical subspecialists. The common philosophy in the treatment of all these disorders is suppression or modulation of the immune system in an attempt to ameliorate pain, disability, or organ dysfunction. Many autoimmune diseases are viewed as having a good prognosis and are treated conservatively. Overall survival for most afflicted individuals is generally accepted as normal, although impairment of vocational or avocational activities may occur.

Another general feature of autoimmune diseases, however, is their diverse clinical course. This may range from a single episode without residual damage, to an indolently progressive disease with significant disability to a rapidly progressive disease with early mortality (in a small subset of patients). It is this latter subset of patients with a high risk of early mortality for whom Alberto Marmont coined the term "severe autoimmune diseases" (SADS).[A. Marmont, Genova, Italy, personal communication] If patients with SADS can be identified before they develop irreversible organ damage, aggressive intervention would be indicated. For this reason, patients with SADS are now being enrolled in experimental protocols of immune ablation and hematopoietic stem-cell rescue at several institutions in the United States (Table 1).


Institutions With Protocols for Immune Ablation and Hematopoietic Stem-Cell Rescue in Patients With Severe Autoimmune Diseases (SADS)

The first successful human allogeneic bone marrow transplants were performed in children with immune deficiencies (severe combined immunodeficiency and Wiskott-Aldrich syndrome).[1] A normal immune system was generated in these children following transplantation of marrow from their unaffected siblings.

The rationale for the use of BMT in SADS is to condition the patient with a chemoradiotherapeutic regimen to ablate the immune and hematopoietic compartments and then rescue the patient from fatal aplasia by reinfusing hematopoietic progenitor cells. The infused stem cells will give rise to new differentiated cells of hematopoietic lineage, including red blood cells, platelets, neutrophils, and immune cells, such as B- and T-lymphocytes, natural killer cells, monocytes, and tissue macrophages.

The concept that BMT can cure autoimmune disease has already been demonstrated in aplastic anemia. In most cases, aplastic anemia arises from immune suppression of hematopoiesis. Depending on a patient's age and the availability of an HLA-matched sibling, initial treatment is either immunosuppression (eg, cyclosporine [Sandimmune] and antithymocyte globulin) or allogeneic BMT. Therefore, the standard of care for one human autoimmune disease, aplastic anemia, is already allogeneic BMT.

Ideally, specific immunosuppression could be targeted to regulate an autoreactive subset of lymphocytes while leaving the overall immune system intact. However, animal studies suggest that once inflammation is initiated against an immunodominant epitope, T-cell clones are recruited against other intramolecular and intermolecular subdominant or cryptic epitopes in the target tissue.[2] This phenomenon of epitope-spreading would argue against any long-lasting effectiveness of specific immunotherapy and in favor of nonspecific immune ablation. Currently, corticosteroids, cyclophosphamide (Cytoxan, Neosar), and azathioprine are examples of broad-spectrum immunosuppressive agents used to treat autoimmune diseases.

Bone marrow transplantation maximizes the dose intensity of immunosuppression to the point of complete immune ablation. In addition, for more than 1 year following either autologous or allogeneic hematopoietic stem-cell reconstitution, the immune system is functionally immunosuppressed. The CD4 count is depressed, and the CD4/CD8 ratio is inverted for 12 to 18 months despite an otherwise healthy graft.[3,4]

Theoretically, BMT may induce lasting remission of an autoimmune disease by: (1) regeneration of a naive immune system, which may remain unresponsive to "self" until reexposure to the original disease-initiating agent(s); (2) generation or infusion of suppressor cells; (3) infusion of genetically distinct allogeneic stem cells, giving rise to T-cells and antigen-presenting cells with different major and/or minor histocompatibility complex surface molecules; and (4) generation of tolerance through exposure of lymphocyte precursors to self-epitopes early in development, possibly resulting in anergy and/or deletion of autoreactive repertoires.

If most autoimmune diseases were inherited as hematopoietic stem-cell defects, rescue with autologous hematopoietic stem cells would not be expected to cure the disease. However, most human autoimmune diseases do not appear to be an environmentally independent defect in hematopoietic stem cells since the majority of monozygotic twins are discordant for clinical disease. Although HLA association with certain autoimmune diseases suggests a genetic predisposition, environmental factors are probably required to initiate these diseases. Even if genetics did play a significant role in some autoimmune disorders, allogeneic stem-cell rescue from an HLA-matched but unaffected sibling might still prevent the disease.

Animal Models of Autoimmune Disease

There are two broad categories of autoimmune diseases in animals: those that arise spontaneously and those that require immunization. In general, spontaneously occurring autoimmune diseases are restricted to inbred strains and arise from genetic defects in the hematopoietic stem-cell compartment. On the other hand, diseases that arise after immunization may occur in a variety of outbred species and are due to priming (ie, activation) of normal, previously naive (ie, unresponsive) lymphocytes. The lymphocytic repertoire of animals that develop disease after immunization is obviously capable of recognizing self-antigens. What is not obvious is how these lymphocytes remain unresponsive until immunized to the self-protein.

Spontaneously Occurring Diseases

Results of Bone Marrow Transplantation in Animal Models of Autoimmune Disease

Examples of spontaneously occurring autoimmune diseases include: a systemic lupus erythematosus (SLE)-like syndrome in Murphy Roth Lab lymphoproliferative (MRL/lpr mice and in the offspring between New Zealand black/New Zealand white mice (NZB/NZW F1 hybrid [B/W])[5-7]; a scleroderma-like illness in Tight-skin (Tsk) mice[8,9] and University of California Davis Line 200 (UCD) L200 chickens[10,11]; an inflammatory bowel disease in cotton top tamarin monkeys[12]; and an islet-cell inflammatory disease similar to type I diabetes mellitus in nonobese diabetic (NOD) mice[13,14] (Table 2). With the exception of the MRL/lpr mouse, the exact genetic defect(s) remain(s) enigmatic.

The MRL/lpr strain of mice develops a massive lymphoproliferative disease characterized by arthritis, glomerulonephritis, vasculitis, and anti-double-stranded (anti-ds) DNA antibody. These mice have a single gene defect that prevents high level expression of Fas, a protein that signals for apoptosis.[15,16] Normal mice express high levels of the Fas protein on CD4/CD8 double-positive thymocytes, inducing apoptosis of potentially autoreactive T-cell clones. T-cells normally upregulate Fas-surface protein when activated, which serves to control a lymphoproliferative response by inducing cell death. In MRL/lpr mice, autoimmunity results from a lack of normal lymphocyte programmed cell death. Transplantation of hematopoietic stem cells from MRL/lpr mice into an unaffected strain of mice results in the MRL/lpr phenotype and early death.

The NZB mouse develops spontaneous hemolytic anemia and a high titer of antierythrocyte antibodies.[5,6] When bred with the phenotypically normal NZW mouse, the offspring (F1 hybrid, B/W) develop a fatal immune glomerulonephritis and a high titer of anti-ds DNA antibody. Although hemolysis may occur, it is not prominent. The genetic defect in B/W mice is unknown, but transplantation of lymphocyte-depleted marrow into a normal mouse from another strain causes fatal immune glomerulonephritis.[7] Similarly, transplantation of lymphocyte-depleted marrow from Tsk[17] or NOD mice[18] into a genetically nonsusceptible strain results in a scleroderma-like illness and diabetes, respectively.

Immunization-Induced Diseases

Animal autoimmune diseases that arise after immunization with the appropriate self-epitope include: adjuvant-induced arthritis,[19] collagen-induced arthritis,[19,20] experimental autoimmune myasthenia gravis,[21,22] experimental autoimmune encephalomyelitis,[23,24] and experimental autoimmune myositis.[25] In all of these diseases, injection of tissue-specific protein in complete Freund's adjuvant initiates disease in susceptible species. The experimental autoimmune encephalomyelitis model will be presented as an example of an autoimmune disease that arises by immunization with target organ homogenate or immunodominant peptide(s).

Experimental autoimmune encephalomyelitis was first discovered as a disease in humans following immunization with the Pasteur vaccine for prevention of rabies.[26] Patients developed an ascending paralysis due to contamination of the vaccine by rabbit central nervous system antigens. Subsequently, it was found that injection of spinal cord homogenate with Freund's adjuvant causes neurologic deficits in a wide variety of species, including mice, rats, rabbits, guinea pigs, and monkeys.

Disease manifestations vary by species. Lewis rats develop a monophasic ascending paralysis with a transient inflammatory spinal cord infiltrate. In the Buffalo rat, experimental autoimmune encephalomyelitis presents as an acute hemorrhagic encephalomyelitis. In the SJL/J mouse, experimental autoimmune encephalomyelitis manifests as an inflammatory, demyelinating, relapsing/remitting disease similar to relapsing/remitting multiple sclerosis (MS).

Further studies have shown that small amino acid sequences of myelin can also initiate experimental autoimmune encephalomyelitis. Several proteins are present in myelin, including proteolipid protein and myelin basic protein. Proteolipid protein is specific to the central nervous system, whereas myelin basic protein is present in both the central and peripheral nervous systems. Immunogenic myelin peptide sequences include proteolipid protein peptide sequence 139-151 or 178-191 and myelin basic protein peptide sequence 84-102. If the animal is immunized with only proteolipid protein sequence 139-151, peripheral lymphocytes during the first relapse proliferate only to proteolipid protein sequence 139-151. During subsequent relapses, epitope-spreading occurs, with lymphocytes proliferating to proteolipid protein sequences 139-151 and 178-191, as well as peptide sequences from other myelin proteins, such as myelin basic protein sequence 84-102.[1]

Use of BMT in Animal Models

Immune ablation and hematopoietic rescue has been attempted in several animal autoimmune disorders (Table 2). Diseases that arise spontaneously and are thought to be secondary to a stem-cell defect have been cured by allogeneic BMT from a strain resistant to the disease. For example, diabetes in the NOD mouse may be prevented by a hematopoietic stem-cell transplant from a nonsusceptible strain.[18] Immune glomerulonephritis, anti-ds DNA antibody, and lymphocytic infiltration of the liver and kidneys disappear in lupus-prone mice after allogeneic transplantation from a nonsusceptible strain.[27-29]

In contrast to stem cell-mediated autoimmunity, animal models of autoimmune disease induced by immunization have been arrested by either allogeneic, syngeneic, or autologous BMT (Table 2). Following autologous BMT, the inflammatory synovitis of adjuvant-induced arthritis resolves.[30,31] After syngeneic BMT in animals with experimental autoimmune myasthenia gravis, anti-acetylcholine receptor antibodies disappear and weakness reverses,[32] while in experimental auto- immune encephalomyelitis, neurologic progression is stopped.[33-36]

Syngeneic BMT from an unimmunized animal, if done before disease onset, prevents experimental autoimmune encephalomyelitis. If performed after the onset of neurologic disease, syngeneic BMT prevents clinical progression and peripheral lymphocytes no longer proliferate to myelin epitopes. Although the immunologic attack may be arrested, remyelination and/or axonal repair is necessary to reverse established neurologic damage. Therefore, depending on the animal and stage of disease, neurologic deficits may not completely resolve.

The results of BMT in animal autoimmune disorders suggest that diseases arising from a stem-cell defect require an allogeneic donor from an unaffected strain to be cured. In contrast, autoimmune diseases that arise from environmental stimuli (ie, immunization) may be cured by a syngeneic or an autologous graft. The role of purging lymphocytes from an autologous graft has not yet been addressed in animal models. Finally, the results of BMT in experimental autoimmune encephalomyelitis suggest that cure of an autoimmune disease may not ultimately benefit the patient since repair of the affected target organ may not occur.


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