Tho-Alfakar Al-Aubodah, Ph.D.
Supervisor(s): Dr. Menna Clatworthy
Award: KRESCENT Post-Doctoral Fellowship
Institution: University of Cambridge, UK
Year: 2026-2029
Project Title: Understanding the roles of tertiary lymphoid structures in CKD progression
Topic(s): Chronic Kidney Disease
Biography
Tho-Alfakar (Tho) Al-Aubodah is a fundamental immunologist with particular interest in autoimmunity. He earned his PhD in Microbiology & Immunology at McGill University where he studied the immune mechanisms underlying idiopathic nephrotic syndrome in children under the supervision of Dr. Ciriaco Piccirillo and Dr. Tomoko Takano. During this time, he developed an expertise in human immunology leveraging cutting-edge single-cell tools to better understand the biological processes that cause immune cell dysfunction in autoimmune diseases. He is currently a postdoctoral fellow in the laboratory of Prof. Menna Clatworthy at the University of Cambridge where he is actively using novel spatial transcriptomics and proteomics technologies on human tissue to unravel immune cell functions in healthy and diseased kidney states.
Tho’s major interests lie with the immune system, and particularly how immune cell functions are intimately tied with the function of the tissue within which they reside. This includes the kidney, where normal and diseased states are associated with distinct immune activities and, indeed, immune-targeting drugs are frequently used in the treatment of many kidney disorders. He aims to establish a research program focused on understanding how immune cell functions vary across human tissue and disease states, helping pave the way for the development of better immune-targeting drugs.
Lay Summary
Background: Chronic kidney disease (CKD) is a growing global concern. It affects about 13% of the global population, including 4.5 million Canadians, and these numbers are only projected to grow. The biggest risk factor for CKD is acute kidney injury – a sudden event that damages the delicate filtering structures of the kidney. While the sources of injury are diverse, they all create a continuously inflamed environment in the kidney that prevents proper healing and, instead, causes scarring composed of abnormal kidney cells. The immune system plays a central role here. Under healthy circumstances, immune cells resident to the kidney survey the organ and participate in repair. However, in the chronically inflamed kidney, these cells begin to promote injury instead. In coordination with injured kidney cells, these resident immune cells begin to call other immune cells from other regions of the body. Amongst these non-resident immune cells are T cells and B cells. These immune cells are unique in that they carry receptors (think locks) that recognize very precise antigens (think keys) on viruses, bacteria, and cancer cells enabling them to respond very specifically to these insult. Within some kidneys of people with CKD, these T cells and B cells cluster together into small organized structures termed tertiary lymphoid structures (TLS). The presence of these structures is often associated with poor kidney outcomes, suggesting that TLS may play a role in CKD progression. TLS are similar in structure to the body's lymph nodes where T cells and B cells normally encounter antigens (keys that fit their locks), become activated, and subsequently mount immune responses against those antigens. In fact, TLS are already known to arise in other organs like the lungs and gut where they enhance immune responses against invading pathogens in an antigen-specific manner. While TLS supporting antigen-specific immune responses is beneficial in the case of infection, it would be detrimental if the antigen was instead present on our cells. This would lead the immune system to attack our own cells causing major injury. We suspect that TLS in CKD are doing exactly this – they act as local hubs that enhance kidney-directed immune responses thereby promoting CKD progression.
Purpose: Blocking CKD progression would prevent millions of Canadians from developing end-stage kidney disease, sparing them from needing life-long dialysis or kidney transplantation. However, due to our poor understanding of the immune processes promoting progression, treatments remain suboptimal. In this proposal, we aim to uncover how the injured cell niche in kidneys promotes the development of TLS and to determine the roles these structures play in disease progression.
Methods: We will obtain kidney tissue from deceased donors across the CKD spectrum. Using advanced experimental and computational tools, we will create a map of these kidneys that will tell us the location of all cells and provide us with unprecedented insight into what these cells are doing, including if they can promote kidney injury. We will also isolate T and B cells from TLS and sequence their receptors (locks) to determine whether they are indeed directing responses against our own kidney cells. We will then relate this information to clinical parameters to determine which cells and cell activities are related to CKD progression.
Anticipated Outcomes: With this high-dimensional map of CKD kidneys, we anticipate to uncover a communication axis between TLS and the surrounding tissue that promote kidney injury. We also hope to discover the environmental cues that support TLS formation.
Patient Engagement: There is currently no patient engagement plan as samples needed for the study have already been bio-banked.
Relevance to Patients/Community: Our proposed work will help uncover pathways involved in CKD that can eventually be targeted to block disease progression. Our work will also provide a better molecular understanding of variability in CKD and support a push towards disease classification based on cause rather than histology.