Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency

Fish, Jonathan D.; Duerst, R.; Gelfand, Erwin W.; Orange, Jordan S.; Bunin, Nancy

doi:10.1038/bmt.2008.308

Cited by 62 publications

(44 citation statements)

References 27 publications

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“…The crucial role of NEMO-dependent NF-κB signaling in the maintenance of intestinal homeostasis is also supported by studies in patients carrying hypomorphic NEMO mutations. These patients usually suffer from severe immunodeficiency and developmental skin defects, but some of these patients also develop colitis [34][35][36][37].…”

Section: Beneficial Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

“…On the contrary, HSCT often worsens pre-existing colitis or even triggers colon inflammation in patients who did not suffer from it before transplantation [36,37], suggesting that impaired NF-κB signaling in non-hematopoietic cells is responsible for colitis development. In light of the findings in NEMO IEC-KO mice, it is reasonable to assume that NF-κB deficiency in the intestinal epithelium is responsible for the pathogenesis of colitis in patients with NEMO mutations.…”

Section: Beneficial Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

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NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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Section: Beneficial Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

Section: Beneficial Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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“…The patient reported by Pai et al 3 had an inflammatory colitis characterized by neutrophilic infiltration before transplant, GVHD following transplant and chronic GI infection following resolution of GVHD. The patient reported by Fish et al 2 showed histologic evidence of GVHD on colonic biopsy following transplant. Neither patient 1 nor patient 2, a patient who had chronic vomiting and failure to thrive before transplant, developed post-transplant GI disease.…”

mentioning

confidence: 95%

“…Initial observations led to widespread concerns that allo-HSCT preparative regimens were poorly tolerated; 1 and, in those who escaped chemotherapy-associated toxicity, there were additional concerns that the underlying somatic tissue defects were exacerbated. 2,3 In particular, it was proposed that introducing a competent immune system into a NEMO-deficient host results in severe, chronic intestinal inflammation and infection as a response to increased translocation of enteric bacteria. 4 As more patients have been identified, it has become apparent that the somatic features that result from hypomorphic IKBKG mutations are quite variable.…”

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confidence: 99%