Identifying Graft Versus Host and Graft Versus Leukemia Allo-Immune Reaction After Stem Cell Transplantation

Kalra, Amit

Identifying Graft Versus Host and Graft Versus Leukemia Allo-Immune Reaction After Stem Cell Transplantation

dc.contributor.advisor	Khan, Faisal Masood
dc.contributor.advisor	Storek, Jan
dc.contributor.author	Kalra, Amit
dc.contributor.committeemember	Lewis, Victor Anthony
dc.contributor.committeemember	Mansoor, Adnan
dc.date	2025-06
dc.date.accessioned	2025-01-20T18:17:37Z
dc.date.available	2025-01-20T18:17:37Z
dc.date.issued	2025-01-15
dc.description.abstract	Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy for hematological malignancies. Two major allo-immune reactions take place in the recipient after HCT: the beneficial graft versus leukemia (GvL) wherein the donor immune cells identify and eradicate the leukemic cells of the recipient and the graft versus host (GvH) where the donor immune cells react against the normal cells of the host causing a debilitating illness called graft versus host disease (GvHD). The primary objective of this doctoral research was to distinguish between GvH and GvL allo-immune reactions by meticulously profiling the immune recovery at multiple time points post-HCT. Immune reconstitution in both adult and pediatric HCT recipients was evaluated at the transcriptomic level via gene expression profiling of 579 immunity-related genes using NanoString technology and at the cellular level through flow cytometric analysis of cell subset counts. Peripheral blood mononuclear cells from HCT recipients were analyzed at Day14, Day28, Day56, and Day84 posttransplant. An immune signature characterized by higher counts of T cells and overexpressed T cell-related genes, was identified in patients who developed acute GvHD grades 2-4 as early as Day14 posttransplant. The gene expression signature showing overexpressed T cell related genes especially CD161 expressing cytotoxic T cells was validated in an independent validation cohort. T cell counts and related transcriptomes were notably higher in cytomegalovirus (CMV) seropositive donor and recipient (D+R+) patients compared to other serostatus groups. The recovery pattern was similar in both adult and pediatric patients. The influence of CMV D+R+ on T cell reconstitution was not significant at early time points (Day 28) but became evident at 2 and 3 months post-transplant. Signatures indicating a lack of GvL response were observed at 3 months (Day 84) post-transplant characterized by downregulated expression of CD8 Tcell genes, including TIGIT and EOMES in patients at high risk of relapse. While this study succeeded in partially differentiating GvH and GvL allo-immune reactions through temporal and differential T cell gene expression profiling, further comprehensive transcriptomic analysis in larger cohorts is essential for a complete understanding of the separation between GvH and GvL.
dc.identifier.citation	Kalra, A. (2025). Identifying graft versus host and graft versus leukemia allo-immune reaction after stem cell transplantation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/120520
dc.language.iso	en
dc.publisher.faculty	Cumming School of Medicine
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Graft versus host disease
dc.subject	Graft versus leukemia
dc.subject	Stem cell transplantation
dc.subject.classification	Immunology
dc.title	Identifying Graft Versus Host and Graft Versus Leukemia Allo-Immune Reaction After Stem Cell Transplantation
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Medical Sciences
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I require a thesis withhold – I need to delay the release of my thesis due to a patent application, and other reasons outlined in the link above. I have/will need to submit a thesis withhold application.