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.