ILC reconstitution and their impact on gastrointestinal tract immunity post lethal irradiation and bone marrow transplant

Albugami, Raef Rashed (2020). ILC reconstitution and their impact on gastrointestinal tract immunity post lethal irradiation and bone marrow transplant. University of Birmingham. Ph.D.

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Abstract

The overall aim of bone marrow transplantation (BMT) is to replenish the damaged haematopoietic system with a healthy and effective system in a timely manner to avoid post-transplant infections. Graft versus host disease (GVHD) and infections are the leading causes of non-relapse mortality following BMT.

In the gastrointestinal tract (GI) tract, Innate lymphoid cells group 3 (ILC3s) are the major producer of IL-22 which plays a critical role in maintaining mucosal homeostasis and tissue repair. The ability of IL-22-producing ILC3s to reconstitute and perform their normal function following BMT has not yet been fully addressed.

Here, we found that IL-22 producing ILC3s, as well as other ILC subsets, remained severely depleted in small and large intestines following BMT. Donor strain and MHC mismatch were the two main factors that dictated the extent of ILC recovery.

As a consequence of the reduced numbers of IL-22 producing ILC3s early immunity against infection, as shown by inability of transplanted mice to control C. rodentium colonisation, was found to be impaired. Furthermore, as we successfully established a mouse model of GVHD, our future aim is to assess the role of IL-22 producing ILC3s in attenuating GVHD severity.

Clinically, these data suggest that an investigation of ILC repopulation of the gut as well as other non-lymphoid tissues may reveal a link between IL-22 producing ILC3 numbers in the gut and the severity of GVHD/susceptibility to gut infections. Furthermore, such ILC3s may be manipulated in order to expand them in situ or elicit improved function which may attenuate gut GVHD pathology whilst leaving the graft versus tumour effect intact.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):