Autologous Hematopoietic Stem Cell Transplantation in Autoimmune Diseases

Claudio Annaloro; Francesco Onida; Giorgio Lambertenghi Deliliers


Expert Rev Hematol. 2009;2(6):699-715. 

In This Article

Abstract and General Aspects


The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies. Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system. Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted. Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys. In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy. Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus. A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia. Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.

General Aspects

The prevalence of autoimmune diseases (ADs) in developed countries ranges between 2 and 7%, along with geographical differences and inclusion criteria.[1–6] Namely, the term AD encompasses a rather wide spectrum of diseases, differing by clinical and possibly pathogenetic features.[5,7,8] A gross conventional distinction recognizes limited/organ-driven and systemic ADs, although a considerable degree of overlap exists between the two groups and some ADs do not fit in either.[4–7,9] In the former group, a 'peripheral' dysfunction is commonly held to play a major role, whereas in the latter, a 'central' immunological compromise is regarded as the pathogenetic clue.

Over the last few decades, investigation on experimental models has allowed a deeper insight to be thrown into the possible pathogenetic mechanisms of some ADs and has prompted the search for newer therapeutic approaches.[10–12] The first step has been favored by the selection of AD-prone strains of laboratory animals, notably New Zealand Black (NZB) mice, who can develop systemic ADs bearing resemblance to systemic lupus erythematosus; in this setting, AD may be transferred to other mice strains through hematopoietic stem cell transplantation (HSCT) from NZB mice, whereas allogeneic HSCT from non-AD-prone mice strains is able to cure ADs in NZB mice[13–15] AD-prone mice strains are considered the paradigm of spontaneous, systemic ADs and the possibility of transmitting or curing AD through allogeneic HSCT is regarded as a hallmark of stem cell disorder.[16] In the opposite corner, other investigators have been able to induce in non-AD-prone mice AD varieties similar to their human counterparts, such as experimental allergic encephalitis (EAE) for multiple sclerosis (MS) and experimental adjuvant arthritis for rheumatoid arthritis (RA)[17,18] The same authors and other groups showed that experimentally induced ADs could be treated with syngeneic HSCT, suggesting an antigen-driven pathogenetic mechanism,[18–21] In non-AD-prone mice strains, various experiments have shown that AD can be transferred from affected to healthy animals by syngeneic HSCT; conversely, syngeneic HSCT from healthy animals was able to cure some, but not all, AD varieties.[22–24] Therefore, these results prompted two gross types of ADs in experimental animals to be distinguished: spontaneously occurring ADs, possibly deriving from a hematopoietic stem cell (HSC) disorder, which can therefore be cured through allogeneic but not syngeneic HSCT; and antigen-induced ADs, as experimental ADs, where autoreactive clones can be silenced by syngeneic HSCT.[17,25–27] Although spontaneous ADs bear resemblance to human systemic ADs and experimental ADs to limited ones, it is unclear whether these models apply to human disease and, in an affirmative case, which pathogenetic model corresponds to each single human AD.[26] Some milestones in the history of experimental ADs are summarized in Table 1 .

Anecdotal reports have shown that patients simultaneously suffering from a hematological disease and an AD could be cured, or at least achieve a durable remission, of their AD as well as their neoplastic disease by means of HSCT.[12,28–30] These results were more commonly achieved after allogeneic HSCT, but similar cases have been reported also after autologous HSCT. Moreover, some AD varieties proved to be more liable than others to derive a benefit from HSCT and, also within the same disease, results were heterogeneous. On the other hand, ADs, both spontaneous and induced by priming agents such as cyclosporine and interferons, are fairly common complications after autologous HSCT, performed either for neoplastic or even ADs.[31–38] However, post-HSCT, ADs are most often clinically self-limiting or are sometimes accounted for by laboratory findings devoid of a clinical counterpart.[39] Worth mentioning is that organ-specific AD prevails among post-HSCT ADs,[40] whereas the preponderance of patients undergoing autologous HSCT because of an AD are affected by systemic varieties of ADs.[41] The lack of a common study design is a main explanation for the contradictory results mentioned to date, but, at the same time, the view is reinforced that AD varieties behave differently as to biology and response to treatment.

Studies on thymic lymphocytes after autologous HSCT have shown that, after a burst sustained by pretransplant memory cells, the organ is repopulated by likely harvest-derived naive T cells, and also the T-lymphocyte repertoire may significantly differ before and after autografting, thus suggesting the possibility of achieving an immune resetting through autologous HSCT, which in turn may exert a potential benefit on AD patients.[42–45]

Finally, in a subset of AD patients with refractory disease life expectancy is so shortened to be comparable with that of oncohematological patients suitable for autografting.[46,47] In these patients, the dismal prognosis might reasonably counterbalance the risk of transplant-related mortality (TRM), at least in the setting of autologous HSCT. Nevertheless, long-term effects of autologous HSCT, notably secondary malignancies and metabolic syndrome, must be weighed in order to make a suited risk–benefit balance.

Relying on the aforementioned experimental data and on the rather feeble clinical evidence, different research groups set sights on finding out whether HSCT, either allogeneic or autologous, might be a suitable strategy to treat ADs.[4,5] Allogeneic HSCT may completely substitute the recipient's immune system with the donor's immune system and exert a graft-versus-autoimmunity effect, leading to cure of the AD.[48] The diffuse application of this approach has been hindered by the fear of a high rate of TRM, which may result in a loss rather than a gain of survival in patients who, even with advanced disease, still have a median life expectancy of 3 years.[46,47] Moreover, graft-versus-host disease (GVHD) may induce clinical patterns mimicking ADs. As a consequence, autologous HSCT has found more extensive acceptance and interest. No different from autologous HSCT for neoplastic diseases, the original purpose was to destroy all autoreactive immune cells,[49] and consequently to achieve 'cure' by inducing tolerance;[50–52] finally, a less troublesome target was identified in its ability to counteract AD progression through a 'resetting' of the immune system.[30,49,53–55]

A further intriguing matter is the proposal of treating chronic extensive GVHD after allogeneic HSCT with 'pseudoautologous' HSCT, for example, with infusion of selected donor-derived cells harvested from the patient.[56] Chronic GVHD is a condition bearing obvious similarities to systemic ADs; the possibility of achieving a response through the above strategy reinforces the notion that autologous HSCT may play a role in the treatment of ADs.[56]

Presently, autologous HSCT is by far the most popular transplant choice for the treatment of ADs.[57] By considering the scientific literature dealing with this issue, it is rather strange to note that the number of comments, editorial and review articles widely outweighs that of clinical trials, with the present article further contributing to this disequilibrium. This may suggest that on this field, controversies outnumber certainties; the matter is made even more intriging by the possible release of new effective drugs that may render even the most widely accepted concepts outmoded. Moreover, the available clinical studies do not outwit Phase I/II trials; indeed, Phase III studies, although underway for some years, have not yet come to definite results. In any case, the term autologous HSCT does not indicate a single homogeneous treatment strategy, but rather encompasses an array of therapeutic options with conspicuous differences in terms of patient selection, HSC mobilization and selection, choice of conditioning regimen and evaluation of response. Therefore, even ongoing clinical trials cannot be expected to answer all the open questions, also including the choice of a reference standard treatment. In the meanwhile, every step in the transplant procedure offers some matter of debate.

As a partial compensation, since 1995 autologous HSCT in ADs represented a subject of intense discussion and monitoring within transplant cooperative groups, notably the European Group for Blood and Marrow Transplantation (EBMT), and of collaboration with rheumatology societies, such as the European League Against Rheumatism (EULAR). This has led to interim surveys offering arguments for provisional guidelines for common practice of HSCT in ADs.[8,58–60]

As further outlined by dealing with the single AD varieties, the best answered question concerns how to evaluate disease activity and response, since in most of the disease varieties a widely accepted scoring system has been defined;[61–64] indeed, these instruments have proved to be effective in comparing disease status before and after HSCT.

An accepted statement is that AD patients amenable to undergo autologous HSCT should have an advanced disease, refractory to several lines of conventional treatment, so that poor quality of life (QoL) and reduced life expectancy minimize the negative effect of TRM. Somewhat contradictory, at least in some AD varieties, such as systemic sclerosis (SS), patients should also do well enough to survive autografting procedure. As a matter of fact, patients with AD and very poor performance status have been shown to have a higher rate of TRM in comparison with cancer patients,[9,65] thus neutralizing the expected benefits of HSCT. Moreover, although autoimmunity obviously exerts a key pathogenetic role in the development of ADs, stopping autoimmunity may not be always equally effective in determining a clinical benefit, since other mechanisms are involved in late disease progression. Moreover, established tissue damage cannot be expected to be reversed by autologous HSCT. For instance, patients with advanced MS, notably primary progressive, may derive scant, if any, advantage from autologous HSCT.

Some additional puzzles may arise as to define a standard rescue treatment for AD patients with advanced disease. The task may be rather easy in AD varieties where several lines of standard treatment are available, as in MS or in Crohn's disease (CD), whereas it is troublesome in diseases such as SS, where the question arises as to whether a standard treatment does exist at all. On the other hand, observational studies defining the disease evolution in cohorts of patients undergoing conventional treatments are lacking.

Peripheral blood is by far the preferred source of HSC and the combination of cyclophosphamide (CTX; 2–4 g/m2) and granulocyte colony-stimulating factor (G-CSF; 5–10 µg/kg) represents the favorite mobilization strategy. It should be emphasized that the mobilization/harvesting phase may be the cause of a not negligible morbidity and mortality rate, attributable both to infectious complications and disease flare-up, although the latter is generally regarded as a complication of G-CSF-alone mobilization.[66,67] Selected (generally positively selected) CD34+ HSCs are definitely more frequently used than unselected, although some reports claim that this strategy could result in a slight increase in TRM.[68–70]

Immunoablative conditioning regimens have been extensively substituted for previous myeloablative ones, frequently including total body irradiation (TBI). Anti-thymocyte globulin (ATG) has gained increasing acceptance along with the shift to less aggressive chemotherapy schedules. The use of ATG and/or CD34+ selection has been linked to an increase in the risk of developing a post-transplant lymphoproliferative disease (PTLD).[69,70]

In general, neurological diseases, notably MS, have been, for a long time, the main indications to autologous HSCT in ADs. More recently, rheumatological diseases, especially SS, have gained increasing interest. Less common indication are immunological cytopenias and miscellaneous disorders. Table 2 summarizes the results of some of the main reports about autologous HSCT in ADs.


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