Graft-versus-host disease (GvHD) remains one of the most significant complications following allogeneic hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and mortality despite advances in conditioning regimens, donor selection, and prophylactic strategies. Understanding the etiopathogenesis of acute and chronic GvHD is essential for improving risk stratification, tailoring prophylaxis, and designing novel targeted therapies.

Acute GvHD (aGvHD) typically develops within the first 100 days post-transplant and arises from a multi-step immunopathological cascade. Conditioning regimens induce extensive tissue damage, releasing danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6, which activate host antigen-presenting cells (APCs). Activated APCs prime donor T cells, leading to the expansion of alloreactive effector T cells. These T cells infiltrate target organs—most prominently the skin, gastrointestinal tract, and liver—mediating tissue destruction via cytotoxic molecules (perforin, granzyme) and further amplification of the inflammatory milieu. Regulatory T cell (Treg) dysfunction, microbial translocation from intestinal damage, and loss of epithelial integrity amplify these effects. Emerging evidence highlights the contribution of innate immune cells, the microbiome, and cytokine networks in shaping the severity and trajectory of aGvHD.

Chronic GvHD (cGvHD), in contrast, is a complex, multifactorial syndrome that shares features with autoimmune and fibrotic disorders. It generally manifests beyond day 100, although temporal overlap with aGvHD is increasingly recognized. The pathogenesis of cGvHD involves sustained immune dysregulation, including aberrant thymic recovery, impaired central and peripheral tolerance, and persistence of autoreactive and alloreactive T and B cells. B cell hyperactivity, autoantibody production, and activation of germinal center–like reactions contribute to chronic inflammation. Crosstalk between T follicular helper cells, pathogenic B cells, and fibroblasts drives tissue remodeling and fibrosis. Key target organs include the skin, lungs, liver, eyes, and mucous membranes, with progressive organ dysfunction severely impacting quality of life. Recent studies underscore the importance of profibrotic cytokines (e.g., TGF-β, PDGF) and aberrant tissue repair pathways in perpetuating cGvHD.

Advances in molecular and cellular profiling have provided novel insights into both acute and chronic disease mechanisms. High-throughput sequencing, proteomic analyses, and microbiome studies have identified candidate biomarkers for early diagnosis, disease monitoring, and therapeutic stratification. These findings are paving the way toward precision medicine approaches, including selective inhibition of JAK/STAT pathways, B cell depletion strategies, adoptive Treg therapy, and microbiota modulation. Despite these promising developments, challenges remain in balancing graft-versus-host effects with graft-versus-leukemia (GvL) activity, underscoring the need for therapeutic interventions that preserve antitumor immunity while mitigating alloreactivity.

In summary, both acute and chronic GvHD arise from complex, overlapping yet distinct immunopathological processes that reflect dysregulated interactions between donor-derived immune cells, host tissues, and the microenvironment. Ongoing research continues to refine our understanding of GvHD biology, which is critical for developing innovative therapies and improving long-term outcomes in allogeneic HSCT recipients.