Immune ablation and stem-cell therapy in autoimmune disease. Experimental basis for autologous stem-cell transplantation

Treatment of rats suffering from florid chronic progressive systemic arthritis or from chronic remitting/relapsing encephalomyelitis with autologous bone marrow transplantation (BMT) is highly effective. This finding was unexpected as the genotype of the bone marrow largely determines the susceptibility of both spontaneous and induced autoimmune diseases in rodents. The success of autologous stem-cell transplantation depends on the completeness of eradication of the effectors of autoimmune disease, in other words activated and memory T lymphocytes. The reviewed experimental data, when translated to the clinic, indicate that the patients should be subjected to a conditioning regimen that induces maximal lymphoablation and that the autologous transplant has to be T-cell depleted.     

Immune ablation and stem-cell therapy in autoimmune disease: Immune ablation and stem-cell therapy in autoimmune disease - Clinical experience

In the past 5 years, around 350 patients have received haematopoietic stem cell (HSC) transplantation for an autoimmune disease, with 275 of these registered in an international data base in Basel under the auspices of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation(EBMT). Most patients had either a progressive form of multiple sclerosis (MS; n = 88) or scleroderma (now called systemic sclerosis; n = 55). Other diseases were rheumatoid arthritis (Ra n = 40), juvenile idiopathic arthritis (JIA; n = 30), systemic lupus erythematosus (SLE; n = 20), idiopathic thrombocytopenic purpura (ITP; n = 7) and others. The procedure-related mortality was around 9%, with between-disease differences, being higher in systemic sclerosis and JIA and lower in RA (one death only). Benefit has been seen in around two-thirds of cases. No one regimen was clearly superior to another, with a trend toward more infectious complications with more intense regimens. Prospective, controlled randomized trials are indicated and being planned.     

Immune ablation and stem-cell therapy in autoimmune disease: Immunological reconstitution after high-dose immunosuppression and haematopoietic stem-cell transplantation

Studies on immunological reconstitution after immune ablation and stem-cell therapy may yield important clues to our understanding of the pathogenesis of human autoimmune disease, due to the profound effects of function and organization of the immune system. Such studies are also indispensable when linking clinical sequelae such as opportunistic infections to the state of immune deficiency that ensues after the treatment. Much has been learnt on these issues from comparable studies in haemato-oncological diseases, although it remains to be proven that the data obtained from these studies can be extrapolated to rheumatological autoimmune diseases. Preliminary results from pilot studies in various rheumatological conditions not only pointed to clinical efficacy of the new treatment modality but also unveiled marked effects on T-cell receptor repertoires of circulating T lymphocytes, on titres of autoantibodies and T- and B-cell subsets.     

Immune ablation and stem-cell therapy in autoimmune disease. Immunological reconstitution after high-dose immunosuppression and haematopoietic stem-cell transplantation

Studies on immunological reconstitution after immune ablation and stem-cell therapy may yield important clues to our understanding of the pathogenesis of human autoimmune disease, due to the profound effects of function and organization of the immune system. Such studies are also indispensable when linking clinical sequelae such as opportunistic infections to the state of immune deficiency that ensues after the treatment. Much has been learnt on these issues from comparable studies in haemato-oncological diseases, although it remains to be proven that the data obtained from these studies can be extrapolated to rheumatological autoimmune diseases. Preliminary results from pilot studies in various rheumatological conditions not only pointed to clinical efficacy of the new treatment modality but also unveiled marked effects on T-cell receptor repertoires of circulating T lymphocytes, on titres of autoantibodies and T- and B-cell subsets.     

Immune ablation and stem-cell therapy in autoimmune disease. Clinical experience

In the past 5 years, around 350 patients have received haematopoietic stem cell (HSC) transplantation for an autoimmune disease, with 275 of these registered in an international data base in Basel under the auspices of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation(EBMT). Most patients had either a progressive form of multiple sclerosis (MS; n = 88) or scleroderma (now called systemic sclerosis; n = 55). Other diseases were rheumatoid arthritis (Ra n = 40), juvenile idiopathic arthritis (JIA; n = 30), systemic lupus erythematosus (SLE; n = 20), idiopathic thrombocytopenic purpura (ITP; n = 7) and others. The procedure-related mortality was around 9%, with between-disease differences, being higher in systemic sclerosis and JIA and lower in RA (one death only). Benefit has been seen in around two-thirds of cases. No one regimen was clearly superior to another, with a trend toward more infectious complications with more intense regimens. Prospective, controlled randomized trials are indicated and being planned.     

Hematopoietic stem-cell transplantation for Hodgkin's disease (HD): current status

Not all patients with Hodgkin's disease (HD) respond to standard chemotherapy and/or radiation, and hematopoietic stem-cell transplantation has been gaining increasing acceptance in the management of HD. Phase II and, to a lesser extent, phase III studies of high-dose chemotherapy and autologous stem cell transplantation carried out at multiple institutions worldwide have proven the feasibility of the procedure and provided extended progression-free survival (and possibly cure) in a sizable number of patients with relapsed or refractory HD. Prognostic factors have been identified by multiple investigators (with response to chemotherapy being the most impressive one) and may ultimately allow a risk-adapted strategy. While early and late treatment-related morbidity and mortality remains an issue, with current supportive care modalities most patients tolerate this procedure with only minor or manageable complications. Disease recurrence remains a problem in many patients, and this can unfortunately occur as late as six or seven years after a seemingly successful transplant. New chemotherapeutic agents and strategies (such as post-transplant maintenance and possibly immunomodulation) will be required to successfully tackle this issue. Allogeneic stem-cell transplantation from HLA-compatible donors has yielded largely unsatisfactory results in the published studies in the literature, despite favorable results in a small minority of patients. Recently, however, newer approaches and strategies (such as the introduction of reduced-intensity, purine analog-based conditioning regimens and possibly cellular immunotherapy in the form of donor lymphocyte infusions) have provided very encouraging early results and seem to brighten the outlook for this procedure.     

High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation for the treatment of solid tumors in adults: a critical review

High-dose chemotherapy (HDCT) plus autologous hematopoietic stem-cell transplantation (HSCT) has been explored in several solid tumors in the attempt to prevent and/or overcome tumor-cell chemo-resistance, based on in vitro evidence of a "dose-response" effect. Preliminary encouraging results from non-randomized trials, led to an increased use of this strategy in the 1990s. Since the end of the nineties, the fraudulent nature of initial reports in breast cancer, the failure of positive prospective randomized trials, HDCT-related toxicities, determined a dramatic decline of interest in this approach. Loss of accrual in ongoing randomized studies was the first consequence, causing the current unavailability of optimal information. From the review of available published data, the use of HDCT with autologous HSCT may improve tumor response rates and/or possibly progression-free survival, especially in some selected patient subgroups. However, this strategy did not demonstrate in almost all cases to produce significantly higher cure rates than standard-dose chemotherapy. Well-designed randomized studies and future strategies integrating HDCT with concomitant and/or subsequent anti-tumor therapies targeted against the residual disease might be suggested in clinically and biologically selected patients.     

Experimental murine and primate models for dissection of the immunosuppressive potential of photochemotherapy in autoimmune disease and transplantation

This paper reviews the results achieved in murine and primate models of autoimmune disease and transplantation. These studies have attempted to clarify the nature and specificity of the response induced by reinfusion of phototreated immunoactive lymphocytes. Results obtained in murine lupus have demonstrated that some of the disease features related to the abnormal proliferation of inducer T cells can be inhibited both prophylactically and therapeutically by exposure to photoinactivated autoimmune splenocytes. Radiolabeling studies performed in normal syngeneic mice have shown that, if immunoactive cells are phototreated and injected, their recirculation pattern is altered, and increased sequestration in the spleen, bone marrow, and kidney is noted. These studies suggest that reinfused, phototreated, antigen-activated lymphocytes may localize in sites where they are available for induction of immune responses. Primate cardiac xenotransplantation models have demonstrated that reinfusion of phototreated autologous leukocytes, administered with cyclosporine A and steroids, mediates enhanced specific suppression of both the cellular and humoral host response to foreign tissue. Taken as a whole, the experimental models suggest that photopheresis may provide a means of inducing specific suppression of immunoactive T cells. This form of therapy may have a role as an immunosuppressive agent in both autoimmune disease and transplantation.     

Experimental autoimmune orchitis: in vitro induction of an autoimmune disease.

Experimental autoimmune orchitis (EAO) can be induced in vitro. Normal lymph node lymphocytes cultured with autologous dissociated testis cells form rosette-like aggregates and later undergo blast transformation and proliferation. These stimulated lymphocytes cause in vivo EAO lesions, when injectd into syngeneic recipients. Moreover, their autoimmune reactivity can be monitored by an in vitro cytostasis assay. Density gradient analysis of the early lymphocyte-testis cultures reveals that the autoimmune reactive lymphocytes are enriched in the rosette populations. It therefore appears that testicular self-antigens are recognized by clonally preformed autologous lymphocytes.     

The autoimmune basis of adrenocortical destruction in Addison's disease

Addison's disease is mainly caused by autoimmune destruction of the steroid-producing cells in the adrenal glands. Key enzymes in steroid biosynthesis have been implicated as the major targets of autoantibodies in this disease. The study of B-cell-dependent autoimmune responses reveals two distinguishable forms of Addison's disease. This should permit very accurate diagnosis of the disease and increase future prospects of disease prevention.     

Comparison of stem-cell recovery in autoimmune and normal strains

The capacity of NZB stem cells to proliferate in vivo was evaluated in two systems which required repopulation of peripheral organs. In both types of depletion systems, stem-cell repopulation after cyclophosphamide treatment or adoptive transfer repopulation in lethally irradiated hosts, it was found that NZB stem cells were hyperproliferating. The increase in proliferating cells was most pronounced in the spleens of NZB mice treated with high-dose cyclophosphamide and in lethally irradiated F₁ mice reconstituted with NZB T-cell-depleted bone marrow. Thus, upon a stimulus to repopulate, NZB marrow stem cells will hyperproliferate in peripheral organs resulting in an increase in cell number. The abnormality in the marrow cells can be observed in young NZB mice when their marrow cells are in an environment which requires recovery and division.     

Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells

Autoimmune diseases that are resistant to conventional treatment cause severe morbidity and even mortality. In the present study we demonstrate that complete remissions can be achieved in refractory polychondritis and systemic lupus erythematosus (SLE), even at advanced stage, with the use of autologous stem-cell transplantation (SCT). Remissions persisted after reconstitution of the immune system. In the treatment of advanced systemic sclerosis (SSc), stable disease may be achieved with autologous SCT.