Gut mucosa barrier preservation by orally administered IgA-IgG to patients undergoing bone marrow transplantation: a randomised pilot study

Abstract

Summary:Intensive cytotoxic therapy with bone-marrow transplantation (BMT) allows a potential cure for haematological malignancies. Protective strategies to minimise haematological toxicities have been successful and currently toxicity to the gastro-intestinal tract is the major cause of treatment-related morbidity and the dose-limiting factor that prevents further dose escalation. In a randomised, placebo-controlled trial we investigated whether an oral immunoglobulin preparation (IgA-IgG) can diminish intestinal toxicity with autologous BMT. IgA-IgG (n = 6) and placebo (n = 7) were orally administered from 1 day prior to the start until 1 week after the termination of the cytotoxic treatment (a total of 14 days). Intestinal toxicity was assessed by a 51 Cr-EDTA absorption test for intestinal permeability and by the clinical criteria laid down by the WHO for the period before the start of the cytotoxic treatment, 1 day prior to stem-cell infusion and 4, 7, 10 and 14 days after stemcell infusion. In the placebo group there was a significant increase in intestinal permeability on day 4 (P Ͻ 0.005) and on day 7 (P Ͻ 0.05) after stem-cell infusion, compared with the baseline, which was not seen for IgA-IgG. In addition, patients receiving IgAIgG had significantly less intestinal permeability on day 4 (P Ͻ 0.05) and on day 7 (P Ͻ 0.05), compared with the placebo group. No significant, positive effect as regards clinical toxicity was observed. Oral administration of IgA-IgG to patients undergoing intensive cytotoxic therapy prior to BMT seems to have a protective effect on the gut mucosa barrier which is normally disrupted by this therapy.

Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia

“…1,29 The integrity of the oropharyngeal mucosa does not necessarily predict the state of distal tissues. 29 Our observations on a relatively small sample confirming previous reports 7,[15][16][17]21 are consistent with this hypothesis. In addition, our observations further re-enforce the independence of the chemotherapy-induced intestinal cytotoxicity and myelotoxicity.…”

“…Our results demonstrate the value of using physiological measures of intestinal barrier function in the design of clinical trials evaluating products such as palifermin, 11 amifostine 10 or even immunoglobulin 16 for the amelioration of cytotoxic therapy-induced intestinal barrier dysfunction and mucositis. It may be prudent to consider the inclusion of these measurements as secondary outcomes in future trials to complement the information provided by more traditional oral and intestinal mucositis scoring systems.…”

“…12,13 The evaluation of drug-related treatment effects have focused primarily on visual estimates of the severity of oropharyngeal mucosa damage and upon nausea, vomiting, abdominal pain and diarrhoea as quantitative surrogates of gastrointestinal damage caudal to the oropharynx using a variety of operator-dependent quantitative and semiquantitative scoring systems. 1 More recently, functional measures of the integrity of the intestinal epithelial barrier using orally administered saccharide or radio-labelled probes have been applied to the study of gastrointestinal mucositis among haematopoietic stem cell transplant recipients 5,7,[14][15][16][17] and in acute myeloid leukaemia. [18][19][20][21] Intestinal permeability may be reflected by an elevated ratio of the concentration of lactulose to mannitol or rhamnose in fractional urinary excretion studies, 21,22 carrier-mediated transcellular absorption by the serum level of a five-carbon sugar, D-xylose, 18 and enterocyte mass by serum citrulline levels.…”

“…26 Although we were able to detect a significant lisofylline-related effect upon permeability, the effect upon xylose absorption was less dramatic. The use of additional probes such as sucrose, 33,34 radio-labelled ethylenaminediamine tetraacetic acid, 15,16 rhamnose, 21 O-methylglucose, 22 citrulline 17,22 or sucralose [34][35][36] might have enhanced the sensitivity for detecting differential treatment effects. Used concurrently, these probes offer the potential to study the differential site-specific damaging effects of cytotoxic therapy on the gastrointestinal mucosa.…”

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

“…Defensins, trefoil peptides and even sIgA-antibodies could offer additional tools to tackle hostile microbes, for example, IgA-IgG administered orally has been shown to reduce gut MBI in patients undergoing intensive cytotoxic therapy. 123 With the means of reliably detecting and monitoring gut MBI at our disposal, the process will graduate from being an expected although unpleasant side-effect with few therapeutic options to a condition that might actually be preventable.…”