**3. Important issues related to allogeneic HSCT for autoimmune diseases**

Treatment of life-threatening autoimmune diseases in animal models with induced or spontaneous autoimmune diseases can be accomplished by a 2-step procedure involving

underwent therapy. With a mean time of observation of 16 months (range 8 - 29 months). No severe complications were observed during the transplantation and in the post transplantation period. Fourteen out of 15 patients became independent of exogenous insulin after the transplantation with median time without exogenous insulin for all these patients of 14 months (range 3 – 29 months). Median day of insulin withdrawal was + 37 (range + 6 to + 103) post transplant. Eleven patients (73%) remain in remission for the median time from transplantation of 16 months. In three patients there was a relapse of requirement for exogenous insulin and the median post-relapse insulin dose for these patients was 0.08 IU/kg of body weight, significantly reduced from pre-transplant dose. The average HbA1c concentration was 11.5 % at diagnosis, 5.88% at 6 months and 5.76% at 12 months after the transplantation. The authors conclude that immunoablation following by autologous HSCT leads to significant reduction for exogenous insulin requirement in all patients and to

Crohn's disease (CD) is a chronic illness, immunologically mediated, of unknown etiology but probably induced by an exposure to intestinal bacteria or their component antigens leading to an excessive T helper type 1–mediated chronic inflammation of the gastrointestinal (GI) tract in patients with genetic susceptibility [**47-48**]. Some patients remain seriously ill with active disease after all therapeutic options have been exhausted [**49-51**]. Moreover, a distinct excessive mortality from CD exists in this group of patients [**52- 55**]. This group of patients may suffer from one or more of the following morbidities: inability to eat, frequent nausea, vomiting, diarrhea, malnutrition, growth retardation in children, fistulas, abdominal pain, extra-intestinal symptoms, psychologic distress from an ileostomy or colostomy bag, iatrogenic addiction to narcotics, toxicities of standard therapies, and multiple surgeries that may lead to short-gut syndrome, chronic total

Appreciating all of the above, it was reasonable to try and use the modality of HSCT in the setup of refractory CD. Thus, 2 main groups, Italian and United States (US), published their data regarding autologous HSCT for refractory CD patients [**56-58**] demonstrating beneficial short- as well as long-term clinical outcome after using the procedure in 4 and 24 patients,

The procedure was safe, without mortality, even in patients heavily pretreated with anti-

Although relapses have occurred in these series of patients after using a cyclophosphamide/anti-thymocytic globulin (ATG) nonmyeloablative regimen, there has been achievements of treatment-free remissions for as long as 5 years, and remission (CDAI < 150, CSI < 12) rates between 70% to 80% for 5 years. The authors emphasize that because approximately 40% of patients with CD develop intolerable side effects or lose response to anti-TNF [**59**], further investigation of stem cell therapy including the role of CD34 graft selection and type of conditioning regimen or other methods to maintain remission without

**3. Important issues related to allogeneic HSCT for autoimmune diseases** 

Treatment of life-threatening autoimmune diseases in animal models with induced or spontaneous autoimmune diseases can be accomplished by a 2-step procedure involving

exogenous insulin independence in early diabetes type 1 in majority of cases.

**2.6 Crohn's disease** 

parenteral nutrition, and liver failure.

respectively, applying nonmyeloablative regimen.

surgery for anti-TNF refractory CD appears warranted.

tumor necrosis factor (TNF) therapy and with ongoing fistulas.

elimination of self-reactive lymphocytes with an immune ablative conditioning regimen followed by infusion of autologous or allogeneic stem cells, respectively. In animal models it was shown that using such a strategy, autoimmunity could be adequately controlled. It is speculated that de-novo development of the T and B cell repertoire from uncommitted progenitor cells in the presence of the autoantigens may be the best recipe for re-induction of self-tolerance, similarly to the normal ontogeny of the immune system during the induction of self tolerance in fetal stage. Reduced intensity conditioning (RIC) is further applied in recent years aiming to diminish regimen-related toxicity by decreasing conditioning regimen intensity compared to conventional myeloablative transplants. In the case of allogeneic transplants for malignant disease, instead of using chemoradiotherapy to achieve disease control, relapse is prevented by an immunological graft versus leukemia (GVL) or graft versus tumor (GVT) effect induced by donor lymphocytes, natural killer cells, and/or dendritic cells infused with the allogeneic graft or after HSCT by infusion of peripheral blood donor lymphocytes. For autoimmune diseases this allogeneic effect may also be applied. Unlike autologous HSCT in which the goal is to suppress and restart the immune system from autologous HSCs, the goal of allogeneic stem cells is twofold. First, to change the genetic predisposition to disease by changing the host's susceptible to the donor's resistant stem cell compartment. Second, to introduce donor's lymphocytes with the capacity to eliminate all residual self-reactive host lymphocytes through a process known as graft versus autoimmunity (GVA) effect, in analogy to GVL in leukemia and GVT in some metastatic solid tumors. It is not clear whether a full chimera, in which all HSCs are reconstituted from the donor, or mixed chimerism, with coexistence of both donor and recipient hemato- and immunopoiesis, is sufficient to control disease. Full donor chimerism in malignancies has been complicated by a high rate of GVHD,

an immune-mediated disease in which allogeneic donor lymphocytes are directed against the whole recipient body, resulting in donor T-cell mediated attack against different organs and tissues, causing significant morbidity and mortality. It is assumed that while suffering from GVHD, the patient has the advantage of GVL or GVT, which is the main goal of the transplant. This rational may holds true, at least partially, in the case of autoimmune diseases. Nevertheless, that means swiching one immunological disease by another one with a very similar mechanism. The only difference is the origin of the attacking T-cells. While in the basic autoimmune disease they are autologous T-cells, in GVHD they are donor-derived T-cells.
