Resetting the immune system in refractory Crohn’s disease: Is autologous hematopoietic stem cell transplantation the way forward?

Abstract

The etiology of Crohn’s disease (CD) remains enigmatic despite recent advances in unravelling mutated genes, such as NOD2/CARD15 and OCTN-1, in subgroups of patients.1Russell R.K. Nimmo E.R. Satsangi J. Molecular genetics of Crohn’s disease.Curr Opin Genet Dev. 2004; 14: 264-270Google Scholar, 2Schreiber S. Hampe J. Nikolaus S. Fölsch U.R. Exploration of the genetic aetiology of inflammatory bowel disease-implications for diagnosis and therapy.Aliment Pharmacol Ther. 2004; 20: 1-8Google Scholar, 3Hugot J.P. Genetic origin of IBD.Inflamm Bowel Dis. 2004; 10: 11-15Google Scholar The chronic up-regulation of the inflammatory response in the gut is the result of complex interactions between the the host and her/his microenvironment consisting of a genetic susceptibility in certain individuals, the immunological system, mucosal cells, life-style-related luminal factors (eg, food-stuffs, drugs), and microorganisms.4Danese S. Sans M. Fiocchi C. Inflammatory bowel disease the role of environmental factors.Autoimmun Rev. 2004; 3: 394-400Google Scholar, 5Elson C.O. Genes, microbes, and T cells - new therapeutic targets in Crohn’s disease.N Engl J Med. 2002; 346: 614-616Google Scholar The dysregulated immune response in CD is mediated by type-1 helper T-cells (Th1), and is characterized by an increased production of proinflammatory cytokines (eg, TNF, IFN-γ, and IL-12), release of chemokines and recruitment of activated leukocytes into affected tissue, resulting in inappropriate and extensive damage of the mucosa and bowel wall.5Elson C.O. Genes, microbes, and T cells - new therapeutic targets in Crohn’s disease.N Engl J Med. 2002; 346: 614-616Google Scholar Impairment in the control of intestinal T-cell function and turnover, most likely caused by defects in normal apoptotic mechanisms, appears to be of significant importance for this dysregulation and for the perpetuation of the pathological inflammatory response.6Peppelenbosch M.P. van Deventer S.J. T cell apoptosis and inflammatory bowel disease.Gut. 2004; 53: 1556-1558Google Scholar When treating severe forms of steroid-refractory and -dependent CD not suitable for surgical intervention, the capacity to induce apoptosis of mucosal T-cells seems to be a crucial factor for drug efficacy. Infliximab, a chimeric monoclonal antibody (mAB) against TNF, exerts profound and rapid anti-inflammatory actions in active CD and is capable of inducing T-cell apoptosis.7ten Hove T. van Montfrans C. Peppelenbosch M.P. et al.Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease.Gut. 2002; 50: 206-211Google Scholar This effect has also been implicated in the long-term action of the antimetabolite azathioprine, to maintain remission in CD.8Tiede I. Fritz G. Strand S. et al.CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.J Clin Invest. 2003; 111: 1133-1145Google Scholar Accordingly, in CD patients, an intrinsic defect in the apoptosis control mechanisms for T-cell survival has been suggested. Interestingly in this respect, a long-lasting remission of CD has been reported for a CD patient infected with HIV after developing AIDS with low CD4+ T-lymphocyte counts.9James S.P. Remission of Crohn’s disease after human immunodeficiency virus infection.Gastroenterology. 1988; 95: 1667-1669Google Scholar In line with these notions, a resetting of the entire immune system by treatment with hematopoietic stem cell transplantation (HSCT), has been put forward as a novel treatment regimen to restore normal immunity without attacking self-epitopes. Experience from such procedures involving CD patients has been limited but intriguing. A patient with CD who received an autologous bone marrow transplantation caused by hematopoietic malignancy and subsequently had a resolution of the inflammatory bowel disease was reported more a decade ago.10Drakos P.E. Nagler A. Or R. Case of Crohn’s disease in bone marrow transplantation.Am J Hematol. 1993; 43: 157-158Google Scholar From Seattle, 4 of 5 patients with CD and leukemia, who received standard ablative (induction) therapy followed by allogeneic bone marrow transplants from healthy donors, were reported to be in clinical remission (3 without immunosuppressive therapy) after a median of 8 years of follow-up.11Lopez-Cubero S.O. Sullivan K.M. McDonald G.B. Course of Crohn’s disease after allogeneic marrow transplantation.Gastroenterology. 1998; 114: 433-440Google Scholar The patient that had a relapse displayed a mixed donor-host hematopoietic chimerism, suggesting that a complete ablation of the former immune system is essential for long-term success. A series from Germany, describing the outcome after allogeneic HSCT in patients with malignant disorders and concomitant CD, also showed that the bowel disorder did not reappear, but length of follow-up was shorter than in the American study.12Ditschkowski M. Einsele H. Schwerdtfeger R. et al.Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation.Transplantation. 2003; 75: 1745-1747Google Scholar If one believes that CD arises from an aberrant response to an environmental factor, for example, an infectious organism, then presumably the eradication of activated clones of effector cells and recovery of naive T cells that will recognize other epitopes would be curative. This could be achieved by autologous HSCT, provided that the conditioning regimen satisfactorily eliminated all autoreactive cells in the recipient and in the stem cell product. In contrast, allogeneic HSCT should be used if immune reactivity is a genetic inevitability as the recipient’s immune function develops with the underlying presumption that elimination of the genetic mechanisms responsible for exaggerated immune responses to luminal antigens will remove the risk of disease recurrence.13Popat U. Krance R. Haematopoietic stem cell transplantation for autoimmune disorders the American perspective.Br J Haemat. 2004; 126: 637-649Google Scholar The genetic determinants of immune-mediated diseases reside both within and without the major histocompatibility complex (MHC) genes, with the non-MHC determinants usually linked to mechanisms of immune regulation. Given the possible heterogeneous pathogenesis of CD, one cannot yet assume that autologous HSCT should be preferred before an allogeneic procedure. Two different ideas have been discussed as the theoretical background of autologous hematopoietic stem cell transplantation (HSCT) for autoimmune disease (AID): either so-called high-dose immune suppressive therapy (HDIT) with an aim to ablate all autoreactive immune cells with the conditioning regimen14McSweeney P.A. Nash R.A. Sullivan K.M. et al.High-dose immunosuppressive therapy for severe systemic sclerosis initial outcomes.Blood. 2002; 100: 1602-1610Google Scholar or a concept of immune “reset” or immune “balance.”15Burt R.K. Slavin S. Burns W.H. Marmont A.M. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation getting closer to a cure?.Blood. 2002; 99: 768-784Google Scholar A complete immune ablation would probably require the graft-versus-autoimmune (GVA) effect of an allogeneic HSCT to be successful.16Slavin S. Nagler A. Varadi G. Or R. Graft vs. autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukaemia and severe psoriasis and psoriasis polyarthritis.Exp Hematol. 2000; 28: 853-857Google Scholar, 17Hinterberger W. Hinterberger-Fischer M. Marmont A.M. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favourably affects outcomes after stem cell transplantation in human autoimmune disease.Bone Marrow Transplant. 2002; 30: 753-759Google Scholar The HDIT will be accompanied by infectious complications, as well as regimen-related mortality. In addition, elimination of the last resting memory lymphocyte with high-dose chemotherapy or chemoradiotherapy is in practice not feasible as experienced from autologous HSCT in malignant diseases. In comparison, immune “balance” would present a dynamic state with constantly fluctuating T-cells between tolerance and immunity. During development, T-cells that bind self with high avidity undergo apoptosis. However, T-cells that fail to recognize a self-epitope also undergo apoptosis. Therefore, circulating T cells in a healthy person normally possess a T-cell receptor repertoire selected to self.18Ashton-Richardt P.G. Tonegawa S. A differential-avidity model for T-cell selection.Immunol Today. 1994; 15: 362-366Google Scholar The conditioning regimen is not intended to destroy every immune cell but rather be sufficient enough to restore immune “balance.” Less intense regimens are also tolerated with fewer infectious complications. Autologous HSCT is today used worldwide in various autoimmune diseases because of the procedure’s greater safety. In this context, the first series with autologous HSCT in patients suffering from severe chronic active CD reported from the group at Northwestern University Medical Center in Chicago,19Craig R.M. Traynor A. Oyama Y. Burt R.K. Hematopoietic stem cell transplantation for severe Crohn’s disease.Bone Marrow Transplant. 2003; 32: 57-59Google Scholar and their extended study in intractable CD-patients reported in this issue of Gastroenterology,20Oyama Y. Craig R. Traynor A.E. Quigley K. Statkute L. Halverson A. Brush M. Verda L. Kowalska B. Krosnjar N. Kletzel M. Whitington P.F. Burt R.K. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease.Gastroenterology. 2005; 128: 552-563Abstract Full Text Full Text PDF Scopus (229) Google Scholar are of great clinical interest. Oyama et al20Oyama Y. Craig R. Traynor A.E. Quigley K. Statkute L. Halverson A. Brush M. Verda L. Kowalska B. Krosnjar N. Kletzel M. Whitington P.F. Burt R.K. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease.Gastroenterology. 2005; 128: 552-563Abstract Full Text Full Text PDF Scopus (229) Google Scholar now present results of a phase I study on autologous HSCT in 12 patients with chronic active, refractory CD. Peripheral blood stem cells were used after T-cell depletion (ex vivo CD34+ cell selection) to achieve quicker engraftment and less toxicity, as well as to deplete activated T-cells. For the latter purpose also equine antithymocyte globulin (eATG) was included in the conditioning regimen (in vivo T-cell depletion), together with high-dose cyclophosphamide. Supportive care against infections was started upon admission including low microbial diet, metronidazole, and ciprofloxacin or, if neutropenia occurred, parental piperacillin/tazobactam until neutrophil recovery. In addition, fluconazole and valacyclovir were continued for up to 6 and 12 months, respectively. Trimethoprim/sulfamethoxazole was given after engraftment until 6 months after HSCT. This significant degree of supportive care is defended taken into account the nature of CD as an inflammatory bowel disease with a high risk for translocation of intestinal microorganisms with septicemia, but certainly also caused by graft manipulation with ex and in vivo T-cell depletion eradicating the cellular immunity. Whether such a broad infection prophylaxis may have influenced the outcome with regard to relapse of CD remains as an interesting question particularly as intestinal microorganisms have been discussed as part of the heterogenous pathogenesis of the disease. The autologous HSCT was well tolerated, with neutrophil and platelet engraftment as expected after high-dose conditioning. No infectious complications or transplantation-related-mortality (TRM) was reported during a median follow-up of 18.5 (range, 7–37) months. Serious adverse events, including risk for fatal opportunistic infections are well-recognized hazards during advanced immunomodulatory and immunosuppressive therapy in IBD. However, in the combined experience from the same institution of more than 70 patients with autoimmune diseases treated with autologous HSCT, no TRM has been reported.21Burt R.K. Traynor A.E. Craig R. Marmont A.M. The promise of hematopoietic stem cell transplantation for autoimmune disease.Bone Marrow Transplant. 2003; 31: 521-524Google Scholar Still, TRM for all autoimmune diseases has been 8.6% in registry data, which is higher than expected (1%–3%). One explanation for the high overall mortality rate of HSCT in autoimmune diseases may be that early trials often include highly selected patients with advanced end-organ dysfunction and/or active and refractory disease with an inherently increased risk.15Burt R.K. Slavin S. Burns W.H. Marmont A.M. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation getting closer to a cure?.Blood. 2002; 99: 768-784Google Scholar The main goal of this clinical series was to prove that general concept of HSCT as a salvage therapy in refractory CD is safe and feasible using very powerful means of induction. The potential of HSCT to suppress, or even ameliorate CD may be even more encouraging, but the results should be evaluated with great care in this respect because half of the patients were followed-up for less than 18 months. Recurrence of CD occurred in 2 patients (2 and 14 months after HSCT, respectively), and only 2 patients achieved a treatment-free clinical remission exceeding 3 years. Moreover, histological and/or radiological lesions compatible with CD were present in most patients, albeit asymptomatic, indicating that a complete structural remission did not occur within the time frame of this study. Allogeneic HSCT from an HLA-matched sibling offers the potential to completely replace a genetically autoimmune disease-prone lymphohematopoietic cells by transferring numerous non-HLA autoimmune disease-resistant genes with the donor cells. The donor’s lymphocytes have also a potential to eliminate residual host hematopoietic and immune autoreactive cells. The benefit of allogeneic HSCT in malignant disease relies on this donor lymphocyte-induced recipient hematopoietic aplasia, termed graft-versus-leukemia (GVL). For autoimmune disease, the same phenomena, graft-versus-autoimmunity (GVA), seems to be responsible for long-lasting effects even after withdrawal of prophylactic immunosuppression. The optimal goal will be the separation of GVA from graft-versus-host disease (GVHD) attacking skin, intestine, and liver with an inflammatory reaction. Nonetheless, the risks of fully ablative therapy and GVHD after allogeneic HSCT cannot be ignored. However, retrospective data showed a superior long-lasting effect of allogeneic as compared with autologous HSCT in severe aplastic anemia (n = 23) and hematologic malignancy (n = 24) concomitant with autoimmune diseases (89% at 18 years vs. 38% at 5 years; log rank, P = .0002).17Hinterberger W. Hinterberger-Fischer M. Marmont A.M. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favourably affects outcomes after stem cell transplantation in human autoimmune disease.Bone Marrow Transplant. 2002; 30: 753-759Google Scholar Interestingly, the GVA effect has still been suggested in experimental autoimmune diseases and may also be present in humans even after non-myeloablative allogeneic HLA-matched transplant.16Slavin S. Nagler A. Varadi G. Or R. Graft vs. autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukaemia and severe psoriasis and psoriasis polyarthritis.Exp Hematol. 2000; 28: 853-857Google Scholar, 17Hinterberger W. Hinterberger-Fischer M. Marmont A.M. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favourably affects outcomes after stem cell transplantation in human autoimmune disease.Bone Marrow Transplant. 2002; 30: 753-759Google Scholar, 22Marmont A.M. Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications.Best Pract Res Clin Haematol. 2004; 17: 223-232Google Scholar The concept of mixed chimerism may be beneficial in ameliorating autoimmune disorders. Mixed chimerism, ie, both recipient and donor hematopoiesis after HSCT, has been shown to induce remission of diabetes and lupus-like autoimmune disease in animal models.23Wang B. Yamamoto Y. El-Badri N.S. Good N.A. Effective treatment of autoimmune disease and progressive renal disease by mixed bone-marrow transplantation that establishes a stable mixed chimerism in BXSB recipient mice.Proc Nat Acad Sci U S A. 1999; 96: 3012-3016Google Scholar In contrast, a mixed chimerism was suggested to be associated with CD-recrudescence in a series with allogeneic transplant.11Lopez-Cubero S.O. Sullivan K.M. McDonald G.B. Course of Crohn’s disease after allogeneic marrow transplantation.Gastroenterology. 1998; 114: 433-440Google Scholar A new venue has risen by experimental data on the capacity of allogeneic HSCT allowing replacement of endothelial cells and fibroblasts from a disease-resistant donor’s hematopoietic stem cell compartment in patients with systemic sclerosis associated with vasculopathy.24Kocher A.A. Schuster M.D. Szabolcs M.J. et al.Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.Nat Med. 2001; 7: 430-436Google Scholar Similarly, adoptive transfer of allogeneic mesenchymal stem cells might carry a potential for healing of IBD as demonstrated for severe acute GVHD of the bowel after allogeneic HSCT for acute leukemia.25Le Blanc K. Rasmusson I. Sundberg B. Gotherstrom C. Hassan M. et al.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lancet. 2004; 363: 1439-1441Abstract Full Text Full Text PDF Scopus (2244) Google Scholar The coming years will see the rapid development of “minitransplantation” using refined non-myeloidablative HSCT procedures which may have the potential to be both safer and more “curative” than contemporary protocols.22Marmont A.M. Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications.Best Pract Res Clin Haematol. 2004; 17: 223-232Google Scholar, 26Burt R.K. Verda L. Oyama Y. Statkute L. Slavin S. Non-myeloablative stem cell transplantation for autoimmune diseases.Springer Semin Immunopathol. 2004; 26: 57-69Google Scholar Further prospective studies are necessary, and are currently ongoing both in Europe27Hawkey C. Stem cell transplantation for Crohn’s disease.Best Pract Res Clin Haematol. 2004; 17: 317-325Google Scholar and the US, to determine the value of HSCT in CD and other autoimmune diseases using innovative conditioning regimens and/or various stem cell sources with or without prior manipulation. Besides opening up a new possible avenue for treatment in severe, refractory CD, the experience of transplantation casts new light on the possible underlying mechanisms in etiology and pathogenesis of IBD. Interestingly, adoptive transfer by hematopoietic cells is recognized in several animal models of IBD. In addition, anecdotal case reports on CD after allogeneic stem cell transplantation for hematological malignancies and after liver transplantation harness the possibility of a genetic abnormality manifested in bone marrow-derived cells being responsible for the chronic intestinal inflammation.28Baron F.A. Hermanne J.P. Dowlati A. et al.Bronchiolitis oblitrans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation.Bone Marrow Transplant. 1998; 21: 951-954Google Scholar, 29Sonwalkar S.A. James R.M. Ahmad T. Hull M.A. et al.Fulminant Crohn’s colitis after allogeneic stem cell transplantation.Gut. 2003; 52: 1518-1521Google Scholar, 30Papadakis K.A. Matuk R. Abreu M.T. et al.Crohn’s ileitis after liver transplantation from a living related donor with Crohn’s disease.Gut. 2004; 53: 1389-1390Google Scholar If true, allogeneic transplantation will be necessary. Widespread clinical application of HSCT in CD is premature at the present time and must await further data to determine whether an allogeneic or autologous source of cells is best as well as development of less toxic myeloid ablative regimens to eliminate risk of mortality associated with the procedure.