THE EFFECT OF CHEMOKINES ON T REGULATORY CELLSFOLLOWING HEART TRANSPLANTATION

UoM administered thesis: Doctor of Medicine

  • Authors:
  • Nouman Khan

Abstract

Heart transplantation (HTx) is now an established therapy for end-stagecardiac failure not responding to medical treatment. Recent decades have seenimproved outcome following HTx due to more effective and targetedimmunosuppressive therapy. However, acute and chronic rejection remains amajor cause of morbidity and mortality. At the same time, immunosuppressivestrategies are associated with significant side effects, including development oftumours. Hence, the induction of immunologic tolerance to alloantigen isconsidered the "holy grail" of transplant research.T regulatory cells (Tregs) are a subset of T cells that appear to suppresscytotoxic cell and initiate tolerance to foreign tissues. The Tregs suppresscytotoxic cells through specific cytokine pathways and cell-cell contact. In-vivoTreg migration has been a matter of debate in recent years. Treg trafficking isgoverned by chemokines, which are small secreted proteins, acting via theirdistinct trans-membrane serpentine receptors.Experimental work has demonstrated an involvement of distinctchemokine pathways in Tregs migration and localization following cardiactransplantation; however, there is paucity of data in humans. I investigated theeffects of chemokines on Tregs in heart transplant recipients through a series ofobservational studies. My study demonstrated that acute rejection followingheart transplantation is associated with a significant elevation of peripheralblood Th1 chemokine levels. I hereby further show that peripheral blood Tregcounts in stable heart transplant recipients are not affected byimmunosuppression but are significantly lower in patients taking statins. I havedemonstrated via in-vitro chemotaxis assays a specific pattern of chemotacticresponse for Tregs and the effector T cells. Using double immunofluorescencestaining and immunostaining, I show for the first time that Tregs may migrate tothe allograft under the influence of CCL17.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • Nizar Yonan (Supervisor)
Award date31 Dec 2011