CBF

(also see mesenchymal stem cells, transfusion, regulatory issues, HIV positive patients, acute radiation injury, adverse events during bone marrow and PBSC donation)

iv. Autoimmune Diseases

See also: Annotated Bibliography, VII. Cord Blood Transplantation in Children, iii. Acquired non-malignant disorders, citation #1

  1. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favorably affects outcome after stem cell transplantation in human autoimmune diseases. Hinterberger W, Hinterberger-Fischer M, Marmont A. Bone Marrow Transplant. 2002;30:753-9.

In treatment of autoimmune disease (AID) with allogeneic stem cell transplants (SCTs, a hypothetical graft-versus-AID activity has been postulated. The authors studied patients with aplastic anemia or a hematological malignancy who suffered from a concomitant AID and who were treated with an allogeneic SCT. Autologous SCTs were also analyzed in patients with malignancies and a concomitant AID. They attempted to detect any superiority of allogeneic or autologous transplants in the treatment of AID.

All reviews, case reports and abstracts available between June 1977 and September 2001 were used and attempts made to update them by e-mail by the corresponding authors. They found that allogeneic SCTs study proved highly effective in obviating the concomitant AID. Only five of 23 cases of concomitant AID failed to respond to the conditioning protocol given prior to an allogeneic SCT. Three patients with Grave's disease pretreated by thyroidectomy or radioiodine and two patients with insulin-dependent diabetes mellitus failed to respond.

Disease-free survival (DFS) after allogeneic SCTs for 23 patients with severe aplastic anemia was 78% at 16 years and survival in unmaintained remission of concomitant AID was 64% at 13 years. DFS after allogeneic SCTs for 24 patients with hematologic malignancies was 87% at 15 years and survival in unmaintained remission for concomitant AID was 70% at 11 years. DFS after autologous SCTs for 24 patients with hematologic malignancies was 48% at 6 years and survival in unmaintained remission for concomitant AID was 29% at 3 years.

Among 30 patients given allogeneic SCTs 19 developed graft-versus-host disease (GVHD) and 11 did not. Upon clinically justified discontinuation of all immunosuppressive therapy, 3/11 patients without GVHD relapsed with their concomitant AID, whereas none of 19 patients with GVHD did so. This difference provides evidence for a graft-versus-AID activity.

Freedom of AID-relapse was superior after allogeneic SCTs compared to autologous SCTs and such data suggest that a graft-versus-autoimmunity effect after allogeneic hematopoietic SCTs mediates elimination of autoimmunity.

  1. Haematopoetic stem cell transplantation for refractory autoimmune cytopenia. Passweg JR, Rabusin M, Musso M, et al.; Autoimmune Disease Working Party of the EBMT. Br J Haematol. 2004;125:749-55 .

The observation in some patients with concomitant autoimmune diseases receiving hematopoietic stem cell transplantation (HSCT) to treat malignancy, animal models using HSCT to prevent and treat severe autoimmune diseases, and theoretical considerations suggest that intensive immunoablation followed by hematopoietic stem cell rescue may improve severe autoimmune disease. Furthermore, allogeneic HSCT may be viewed as an attempt to cure autoimmune disease by replacing the immune system.

This is a descriptive study of patients reported to the European Group for Blood and Marrow Transplantation (EBMT) registry undergoing autologous or allogeneic HSCT for refractory autoimmune cytopenias. The registry holds data on 36 patients receiving 38 transplants; the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune hemolytic anemia, Evans' syndrome, immune thrombocytopenia, pure red cell aplasia, pure white cell aplasia, or thrombotic thrombocytopenic purpura. Patients had longstanding disease having failed multiple prior treatments.

Among 26 evaluable patients treated with autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response.

The patients selected for allogeneic HSCT were younger and had a shorter disease duration and less pretreatment, reflecting the general tendency to select young patients with severe disease for allogeneic transplantation.

The authors concluded that autologous and allogeneic HSCT may induce a response in a subset of patients with refractory autoimmune cytopenias albeit at the price of considerable toxicity.

  1. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions. Tyndall A, Saccardi R. Clin Exp Immunol. 2005;141:1-9 .

The authors comment that over the past 20 years sporadic case reports and small series of patients have been published suggesting that autoimmune diseases (AD) may be cured by HSCT. The initial reports were allogeneic transplants, but later similar cases appeared after autologous transplant. These reports, together with animal model data prepared the ground for phase I/II studies in humans.

This report reviews data regarding autologous HSCT, a technique applied to severe AD cases after several international meetings resulted in published consensus guidelines. As agreed, only patients should have been transplanted in whom conventional therapy had failed, but in whom still enough reversible pathology remained to ensure a decent quality of life if treatment were successful.

Results of phase I/II studies in multiple sclerosis, scleroderma, rheumatoid arthritis, systemic lupus erythematosus, severe refractory immune cytopenias and other ADs are presented. The authors conclude that the role of hematopoietic stem cell transplantation in the treatment of severe, therapy refractory AD remains experimental but is sufficiently encouraging to proceed to randomized prospective trials in the major diseases: scleroderma, rheumatoid arthritis, multiple sclerosis, and soon juvenile idiopathic arthritis and SLE. In all sub-groups some patients have achieved long-term (up to 8 years) drug free remission, indicating that at least in these individuals a control of the autoimmunity was possible extending beyond the period of general immune suppression. It is likely that when performed early in non-critically ill AD patients with a poor prognosis but still reversible disease, a positive impact on the natural history of the AD will be possible.

Further prospective randomized controlled clinical trials are required to establish the place, if any, HSCT has in treatment of AD. Further, basic science programs are necessary to explain the pathophysiological mechanisms of these immune modulating strategies.

  1. Hematopoietic stem cell transplantation for multiple sclerosis. Burt RK, Cohen B, Rose J, et al. Arch Neurol. 2005;62:860-4.

Hematopoietic stem cell transplantation (HSCT) was proposed as a treatment for multiple sclerosis (MS) in 1995 based on favorable results in animal models including experimental autoimmune encephalomyelitis. In general, early trials suffered from higher than anticipated toxic reactions including treatment-related and disease-related mortality, continued loss of brain volume as seen on magnetic resonance imaging (MRI), and, at least in some patients, continued progressive disability despite marked attenuation or absence of gadolinium-enhancing lesions on MRI. Learning from these experiences, second-generation transplantation trials for MS are using MS-specific nonmyeloablative transplantation regimens and selecting for active relapses despite the use of interferon treatment in patients with less accumulated disability.

The authors discuss the rationale of HSCT, animal results, mobilization of HSCs from patients with MS, ex-vivo HSC selection, conditioning regimens, and the results of first and second-generation HSCT protocols.

They suggest that, while still preliminary, results using second-generation nonmyeloablative HSCT regimens are encouraging with minimal treatment-related morbidity and improvement in Expanded Disability Status Scale (EDSS) scores. The following 3 variables seem important in predicting the benefit and minimizing the toxic effects from an autologous stem cell transplantation in patients with MS: the selection of patients who still have inflammatory disease (i.e., gadolinium enhancement on MRI and/or frequent active relapses), treatment early in the course before the onset of significant irreversibly progressive disability, and the use of a safer lymphoablative but nonmyeloablative HSCT conditioning regimen.

  1. Treatment of severe autoimmune disease by stem-cell transplantation. Sykes M, Nikolic B. Nature. 2005;435:620-7.

This is a comprehensive review of the state of the art of hematopoietic cell transplantation (HCT) for severe autoimmune disease.

So far, auto-HCT has been generally preferred over allo-HCT because of the increased toxicity, and the potential for rejection and GVHD in allo-HCT. Nevertheless, allo-HCT has been associated with durable complete remission in a small number of patients treated for malignant diseases with coincidental autoimmune disorders. Most recently, several groups have applied non-myeloablative or reduced-intensity conditioning protocols for allo-HCT to the induction of transplantation tolerance and re-establishment of self-tolerance in animal models of autoimmune disease.

Animal models provide the rationale for HCT. The transfer of immune diseases with hematopoietic cells has been demonstrated for many autoimmune diseases, including other murine models of systemic lupus erythematosus (SLE), experimental autoimmune encephalomyelitis (EAE), adjuvant arthritis, antiphospholipid syndrome and type 1 diabetes. Thus, susceptibility to autoimmune diseases appears to reside in hematopoietic cells.

The superior efficacy of allo-HCT over syngeneic or auto-HCT in some animal autoimmune disease models suggested that allogeneic donor T cells eliminate autoreactive host lymphocytes, and therefore mediate a form of immunotherapy termed graft-versus-autoimmunity.

Several mechanisms by which HCT might treat autoimmunity are reviewed in depth and are unlikely to be mutually exclusive. These include (1) Immunomodulation by immunosuppressive conditioning and auto-HCT, (2) Immune-mediated destruction of autoreactive T and B cells, (3) Deletion of alloreactive and autoreactive TS cells in the thymus, (4) Anergy and deletion of peripheral auto- and alloreactive T cells (5) Tolerization by regulatory T cells, (6) Tolerization of autoreactive and alloreactive B cells, and (7) Tolerance induction through HSC chimerism.

The authors conclude by stating that the ultimate role for allo-HCT in the treatment of autoimmune disease will be better defined by results of ongoing auto-HCT trials, and by an improved understanding of disease pathogenesis, the genetic defects underlying different forms of autoimmune disease, and the mechanisms by which HCT may tolerize memory T and B cells. Further, HCT might also allow regeneration of tissues that are destroyed by autoimmune disease. However, the real potential of tissue regeneration from HSC to cure autoimmune disease is controversial and remains an area of intense investigation.

  1. Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective. Hough RE, Snowden JA, Wulffraat NM. Br J Haematol. 2005;128:432-59.

This review provides a comprehensive update on the efficacy and toxicity of hemopoietic stem cell transplantation (HSCT) in severe autoimmune disease. The potential of (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for hematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. Future directions in the context of other evolving therapies are discussed. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases, and phase III clinical trials are in progress for some diseases.

  1. Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute-Sponsored International Workshop, Bethesda, MD, March 12 and 13, 2005. Griffith LM, Pavletic SZ, Tyndall A, Bredeson CN, Bowen JD, Childs RW, Gratwohl A, van Laar JM, Mayes MD, Martin R, McSweeney PA, Muraro PA, Openshaw, Saccardi R, Sandmaier BM, Forman SJ, Nash RA; Workshop articipants. Biol Blood Marrow Transplant. 2005;11:862-70.

This is a report of a 11⁄2 day National Institute of Allergy and Infectious Diseases (NIAID) and National Cancer Institute (NCI)-sponsored workshop. The primary objective was to critically explore and identify the rationale for clinical trials of allogeneic HCT in autoimmune diseases, with particular emphasis on multiple sclerosis (MS) and systemic sclerosis.

Rationale: Allogeneic HCT is a curative therapy for several malignant and nonmalignant disorders. Among other mechanisms of action, the allogeneic graft exerts an immune-mediated graft-versus-host effect that is important for successful engraftment and may be responsible for the poorly understood clinical phenomenon called the graft-versus-autoimmunity effect. Animal models of autoimmune disease, extensive experience in patients with aplastic anemia, and a series of published clinical case reports in patients with systemic autoimmune disease provide evidence that allogeneic HCT may cure patients with autoimmune disease, but safety and response durability are still being investigated. The introduction of lower-intensity nonmyeloablative conditioning regimens and better prevention and treatment of both GVHD and infections have improved the safety profile of allogeneic HCT.

Disease candidates and patient populations were reviewed as were transplantation regimens, stem cell sources, graft manipulations, the role of chimerism and donor lymphocyte infusions. The article concludes with a list of 11 "Issues in clinical trial designs."

[Comment: All in all, this publication provides little valuable information, reiterates information well known to transplant physicians, and offers generalities.]
  1. Target populations in allogeneic hematopoietic cell transplantation for autoimmune diseases--a workshop accompanying: cellular therapy for treatment of autoimmune diseases, basic science and clinical studies, including new developments in hematopoietic and mesenchymal stem cell therapy. Griffith LM, Pavletic SZ, Tyndall A, Gratwohl A, Furst DE, Forman SJ, Nash RA. Biol Blood Marrow Transplant. 2006;12:688-90.

To consider the problem of patient selection in more detail than in the previous citation, physicians met in a workshop in October, 2005. The group agreed that allogeneic HCT offers the potential to effect remission and/or cure of refractory autoimmune diseases as suggested by case reports and follow-up of patients with autoimmune disease who received this therapy for another primary indication. A significant number of patients with severe autoimmune disease fail to respond to conventional therapies and none of these are curative.

It is desirable to enroll patients in studies at a time during their disease course when the disorder is most likely to respond to HCT and who are optimal transplantation candidates.

Current autologous HCT protocols in multiple sclerosis target those patients who have early relapsing remitting disease with features indicating high risk for evolution to secondary progressive disease. A more accessible an practical population for pilot studies of allogeneic HCT for multiple sclerosis might include those patients who are in the process of developing or have just developed secondary progressive disease.

When developing end points for clinical trials of allogeneic HCT for autoimmune disease, the concept of "extended remission " off immunosuppression and "cure" of disease should be considered because the definition of benefit may vary depending on the disease and type of patients who are enrolled.

[Comment: As in the previous citation, most of the information provided is in the form of well known generalities.]
  1. Allogeneic bone marrow transplantation for autoimmune disease--the jury is still out. Tyndall A. J Rheumatol. 2006;33:644-6.

Apparently inspired by the report of 2 cases of rheumatoid arthritis with sustained full clinical remission up to 19 and 20 years following allogeneic HSCT for gold and penicillamine-induced severe aplastic anemia (see citation J below), the author reviews the present status of allogeneic HSCT for autoimmune disease.

The concept of HSCT for severe autoimmune disease evolved from supportive animal data and reports of patients receiving an HSCT for conventional indications in whom a coincidental autoimmune disease was present and improved.

The author reviews basic concepts of HSCT including the fact that the source of stem cells may be bone marrow, peripheral blood or cord blood, conditioning regimens may be myeloablative or reduced in intensity, and GVHD may result in significant morbidity and mortality. The principle behind HSCT for autoimmune disease is that through hematopoietic stem cell support a threshold of immunosuppression can be surpassed that was previously not possible due to marrow toxicity, and that this may allow the immune system to "reset" to a tolerant state.

The results so far on mostly autologous HSCT-treated patients suggest this to be so in over 30%, which is especially gratifying in systemic sclerosis (SSc) with patients followed up 10 years post-transplant. Controlled studies are underway in Europe for SSc MS and Crohn's disease; and in the US for SSc, MS and systemic lupus erythematosus (SLE). It is recognized that allogeneic protocols may be more effective in some patients.

While the autologous HSCT program for autoimmune diseases is progressing, it is clear that not all patients respond, or they respond with later relapse; and acute organ toxicity is an issue, especially relating to TBI and cyclophosphamide in SSc.

In the end, the "holy grail" of tolerance induction without long-term immunosuppression is in our sights but whether this will be autologous or allogeneic and which protocol will be superior is currently not clear.

  1. Twenty-year remission of rheumatoid arthritis in 2 patients after allogeneic bone marrow transplant. Lowenthal RM, Francis H, Gill DS. J Rheumatol. 2006;33:812-3.

This is a brief report which describes 21 and 19 year follow-up of 2 patients with severe rheumatoid arthritis (RA) who in 1984 and 1986 underwent allogeneic bone marrow transplantation (BMT) after full myeloablative conditioning, for therapy-induced aplastic anemia. Regarding the arthritis, both patients are well, taking no medications, and free of signs or symptoms of active RA. (Patient 1 was in remission of her previously severe RA at the time of the transplant, but patient 2 had active RA at the time of transplant.) One patient is in excellent health overall, while the other has coronary artery disease and chronic obstructive pulmonary disease attributable to smoking. Both patients had evidences of GVHD and the authors suggest that this may have played a role in the apparent cure of their RA. The authors comment that most recent reports of autologous or non-myeloablative transplants for severe RA indicated that responses, although common, are generally short-lived; that is, of the order of 6-12 months.

The authors suggest that these cases raise the possibility that allogeneic BMT may be a curative treatment for severe RA.