Menachem Bitan

*Pediatric Blood and Marrow Transplantation & Immunotherapy Program Department of Pediatric Hematology/Oncology, "Dana" Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel* 

#### **1. Introduction**

368 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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#### **1.1 Autoimmune diseases**

Autoimmune diseases (AD) are individually rare, but together they affect approximately 5-8 percent of the population in Western countries [1-2]. They are usually defined as a clinical syndrome caused by the activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause. In recent years it is well established that low level of autoreactivity is physiologic [3] and crucial to normal immune function. Autoantigen helps to form the repertoire of mature lymphocytes, and the survival of naive T cells [4] and B cells [5]. Thus, the assumption is that lymphocytes evolved not to distinguish self from foreign, but rather to respond to antigen only in certain microenvironments, generally in the presence of inflammatory cytokines [6].

There are several classifications of AD. They may appear to be either systemic (as in the case of systemic lupus erythematosus) or organ-specific (as in the case of type 1 diabetes mellitus). Another classification distinguishes between diseases in which there is a general alteration in the selection, regulation, or death of T cells or B cells and those in which an aberrant response to a particular antigen, self or foreign, causes autoimmunity.

Susceptibility to AD is multifactorial with genetic and enviromental factors being dominant together or alone in each of the syndromes. Infectious-derived antigens are also well known triggers for autoimmunity. Molecular mimicry has clearly been demonstrated in herpes keratoconjunctivitis in mice. T cells that react to the viral protein UL6 cross-react with a peptide derived from a corneal antigen [**7**]. Rheumatic fever represents an autoimmune response triggered by streptococcal infection and mediated by cross-reactivity between streptococcal and cardiac myosin [**8-10**]. In autoimmune diabetes, T-cells recognize both a peptide derived from the autoantigen glutamic acid decarboxylase and a highly analogous peptide from coxsackievirus P2-C protein [**11**], and in Guillain–Barrי syndrome antibody cross-reactivity has been demonstrated between human gangliosides and lipopolysaccharides of Campilobacter jejuni [**12**]. Drugs like Procainamide can also alter the immune repertoire. Finally, foreign substances may act as haptens and render autoantigens immunogenic.

Haematopoietic Cell Transplantation and Immunotherapy

is generally resistant to conventional therapies [21].

to act in re-myelinization and neuron repair.

transplantation and conditioning regimens used [**22**].

**2.2 Rheumatoid arthritis** 

in 80% of patients with RA [23].

**2. HSCT in specific clinical indications** 

**2.1 Multiple sclerosis** 

for Autoimmune Diseases in Children and Adults 371

Multiple sclerosis (MS) is an organ-specific AD mediated by T cells triggered against structural components of myelin in the central nervous system (CNS). Subsequent to inflammation in the CNS, demyelinization and loss of axons may occur, resulting in interruption of the electrical signal. Most MS patients present episodic relapse and improvement, known as relapsing-remitting MS, followed by a phase called secondary progressive MS. There is yet another form of MS known as primary progressive MS, which

Available treatments for MS are not curative. They are able to reduce inflammation in the CNS and to delay the advance of the disease, but disease control is frequently unsatisfactory. The use of stem cells in the treatment of MS is based on the immunosuppressor and immunomodulatory effects of HSCT, which may favor the immunological balance [21]. Furthermore, the multi-focal nature of MS makes the injection of stem cells into each affected site impracticable, which means that the cells need to be attracted to the pathological areas. The intravenous administration of stem cells may be an alternative in MS and other neuroinflammatory conditions, in which there is permeability of the hematoencephalic blood brain barrier in the inflammatory areas. Moreover, the discovery that stem cells are capable of reaching the CNS and of transdifferentiating or acquiring oligodendrocyte and possibly neuronal properties, suggests that they may be able

Intensive immunosuppresion followed by HSCT has been suggested as potential treatment in severe forms of MS. Since 1995, more than 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least for 3 years posttransplant. Magnetic resonance revealed the capacity of autologous HSCT to suppress or markedly reduce gadolinium-enhancing lesions. The progression of brain atrophy declined after two years post-HSCT. The profound immunological changes following autologous HSCT may result in restoration of self-tolerance. Relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy seem the best candidates for transplantation. Transplant-related mortality was 6% in the first European Group for Blood and Marrow Transplantation (EBMT) report and 5.3% in the second one. No deaths were reported since 2001. Very high-intensity conditioning regimen is associated with higher risk of toxicity without significant increase in efficacy. The effects of transplantation and transplantation-related morbidity are dependent on patient-selection, time of

Rheumatoid Arthritis (RA) is a systemic AD that, in the long term, can lead to irreversible destruction of the joints, loss of mobility, as well as a reduction in both the quality of life and life span. Cellular and humoral immune responses can contribute to the development of lesions. Rheumatoid factor, an autoantibody specific to the Fc region of human IgG, is found

In a retrospective analysis summarizing the European experience of the first 78 registered patients, a significant improvement was demonstrated, with 67% achieving an American

#### **1.2 Hematopoietic stem cell transplantation**

Hematopoietic stem cell transplantation (HSCT) is a well established modality for the treatment of several hematological diseases; however, it can also be used for the treatment of severe forms of immunological diseases.

Conventional AD therapy is effective in most patients, but some patients are resistant to the anti-inflammatory and immunosuppressive agents used or are only capable of responding to high doses of such medicines, which are toxic. In such cases, bone marrow (BM) reconstitution is required. Thus, high doses of immunosuppressants, followed by HSCT, have become an alternative treatment for many diseases involving the immune system. These include multiple sclerosis (MS), systemic sclerosis (SS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and systemic lupus erythematosus (SLE) [13-14].

The application of HSCT to the treatment of AD has been studied since the 1970s. The success of this approach has been widely demonstrated in animal models as well as in BM transplant patients who were shown to also have concomitant AD. For example, an allogeneic HSCT which was intended to cure aplastic anemia in 2 patients with concomitant RA, resulted in the complete remission of RA for at least 11 years [14].

The rationale of using HSCT in autoimmune diseases is to achieve the complete ablation of the aberrant immune system and to regenerate a new and antigen-naive immune system. The more widespread use of transplantation is hindered by the risks associated with cytoreductive treatments necessary to create space for the transplanted hematopoietic stem cell population and by the slow kinetics with which immune competence is restored following transplantation. Mild conditioning regimens may be insufficient to create space for donor stem cells. However, fully myeloablative approaches using irradiation and chemotherapy agents may associate with severe side-effects such as the risk of oncogenic DNA damage. Nevertheless, unlike malignancies where any visceral organ impairment is a contraindication to HSCT, disease-related organ dysfunction is often the indication for HSCT of autoimmune disorders. For this reason, the regimen must also avoid further injury to the disease-affected organ. For example, myeloablative agents such as bleomycin, BCNU (carmustine), and radiation that are complicated by pulmonary fibrosis would not be the ideal conditioning agents for a disease such as scleroderma in which a major cause of death is related to pulmonary fibrosis and pulmonary artery hypertension [**15**].

The stem cell graft may be syngeneic (from identical twin), allogeneic (from a donor with identical human leucocyte antigen – HLA – system), or autologous (from the patient). In autologous setting, the goal of regenerating a new, antigen naive immune system, from the patient's own hematopoietic stem cells requires the re-emergence of thymic educated T cells. Therefore, the goal of the conditioning regimen would focus on immune ablation rather than myeloablation [16-17]. Allogeneic grafts are associated with complications such graft versus host disease (GVHD) or graft rejection. GVHD contributes to the elimination of the host's aberrant immune system and thus theoretically, makes allotransplant a better option in the treatment of autoimmune diseases [18]. However, the HSCT treatment related mortality in hematological diseases is higher following allogeneic grafting (15–35%) than following autotransplant (3–10%). Because of these high mortality rates following allotransplants, the autologous method could prove to be a better alternative in autoimmune patients, too [19-20]. On the other hand, in recent years the transplant related mortality (TRM) is extremely low due to better peri-transplant care. Thus, it may shift again for the allo-transplant as the better choice for autoimmune diseases, in the coming years.
