DISCUSSION:
The only curative therapy for many primary immunodeficiencies is HSCT. aGvHD is a serious and potentially fatal complication of HSCT with an incidence of nearly %50. Furthermore, involvement of the lower gastrointestinal (LGI) tract is associated with a poor prognosis.1, 2
Based on murine studies, aGvHD pathophysiology is thought to include neoangiogenesis, intestinal tract infiltration by innate myeloid cells (neutrophils and monocytes), innate and adaptive immune responses triggered by sterile damage-associated molecular patterns (DAMPS) and pathogen-associated molecular patterns (PAMPS).15 Also since the early 1980s, the intestinal injury in aGvHD had been identified to cause protein-losing enteropathy characterized by faecal AAT elevation. 16,17
AAT is a circulating 52-kDa glycoprotein that is produced mainly by the liver. 4 It acts as an endogenous serine protease inhibitor, inhibits neutrophil elastase and protects especially lung and liver tissues from destruction.4,7,9 Plasma-derived and recombinant AAT are devoid of antielastase activity, but recently, its anti-inflammatory, immunomodulatory and tolerogenic features have been identified; it decreases the production of pro-inflammatory cytokines (IL-6, IL-8, TNF-ɑ, IL-1ß), increases differentiation and maturation of Foxp3+ regulatory T cells (Tregs).6,7,9Because of these features, it was a candidate for GvHD treatment. After successful treatment of GvHD in murine models 4,5, clinical trials with humans have begun.
Clinical trials revealed different results. In the first phase 1/2 clinical trial 6, AAT was used as the first-line therapy after corticosteroids and the overall response rate (ORR) was found 66% (8/12 patients) with a 33% complete response rate (CRR). In another phase 2 study with 40 patients, confirming the first trial, ORR and CRR were 65% and 35%, respectively.7 AAT serum levels and proportion of Tregs were found elevated in both studies. In another study 8, AAT was used both as a first-line (4/7) and a subsequent line (3/7) of therapy in seven patients. Unfortunately, none of the patients achieved a CR. This was attributed by the authors to the fact that all patients had grade III-IV GvHD. In a recent study, AAT was used as both a first-line (6/16) and a subsequent line (12/16) of therapy in 16 patients.9 ORR was 44%, CRR was 27%. Similar to the previous studies, serum AAT levels were elevated, though the proportion of Tregs was decreased. All of our patients received AAT as a subsequent therapy and had various responses. Differently from the literature, only one of our patients (P1) had elevated serum AAT levels, despite in all of them, proportions of Tregs were found elevated.
As SR-aGvHD is a major cause of mortality after HSCT, there are studies with pre-emptive treatment with AAT, too. 10Unfortunately, in a recently published study, AAT wasn’t found to improve GvHD outcomes.10 There are recruiting clinical trials both for prevention (NCT03805789) and primary treatment (NCT04167514) of GvHD with AAT. We hope that further studies both with children and adults will help to overcome the disease.