Alloantigen presentation and graft-versus-host disease: fuel for the fire

Abstract

Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloantigen is presented to donor T cells to generate graft-versus-host disease (GVHD) represents an attractive therapeutic strategy to prevent morbidity and mortality after SCT and has been increasingly studied in the last 15 years. However, the immune activation resulting in GVHD has no physiological equivalent in nature; alloantigen is ubiquitous, persists indefinitely, and can be presented by multiple cell types at numerous sites, often on incompatible major histocompatibility complex, and occurs in the context of intense inflammation early after SCT. The recognition that alloantigen presentation is also critical to the development of immunological tolerance via both deletional and regulatory mechanisms further adds to this complexity. Finally, GVHD itself appears capable of inhibiting the presentation of microbiological antigens by donor dendritic cells late after SCT that is mandatory for the establishment of effective pathogen-specific immunity. Here, we review our current understanding of alloantigen, its presentation by various antigen-presenting cells, subsequent recognition by donor T cells, and the potential of therapeutic strategies interrupting this disease-initiating process to modify transplant outcome.

Sequential allogeneic and autologous CAR-T–cell therapy to treat an immune-compromised leukemic patient

“…Alternatively, long-term chemotherapy may have depleted host antigen-presenting cells and mitigated the development of GVHD. 19,20 In summary, an unselected CAR-T strategy with sequential alloand auto-CAR-T infusions successfully mediated remission of a relapsed/refractory B-ALL case. This sequential strategy resulted in CR without severe adverse effects.…”

“…19 Here, the lack of GVHD may be attributed to the highly immunodeficient state and the preconditioning regimen, which resulted in marked reduction of host immune cells. Furthermore, continuous therapeutic and prophylactic use of TNF-a antagonist (etanercept) during CAR-T expansion may have suppressed GVHD (L.-J.C. and J.-P.Z., unpublished observation).…”

Myelodysplastisches Syndrom, akute Leukämie und Stammzelltransplantation

“…Durch diese Entzündungsreaktion werden Antigen-präsentierende Zellen aktiviert, die dann wieder Spender-T-Zellen aktivieren können. Aktivierte zytotoxische T-Zellen und weitere Effektorzellen des Spenders führen dann zu schwerer Gewebeschädigung [30]. Risikofaktoren stellen neben HLA-Unterschieden zwischen Spender und Empfänger ein unterschiedliches Geschlecht, höheres Alter und weibliche Spender mit vielen Kindern dar [29].…”

“…Betroffen sind v. a. Haut (bis zur Blasenbildung), Leber (Bilirubinanstieg) und Gastrointestinaltrakt (Diarrhöen), aber auch die Augen und die Mundschleimhaut. Da die komplette T-Zell-Depletion auch den antileukämi-schen Effekt beeinträchtigt [30], stellt die Immunsuppression mit einem Calcineurininhibitor und der kurzzeitigen Gabe von Methotrexat (in Chemotherapiedosis) nach allogener Stammzelltransplantation die wesentliche prophylaktische Maßnahme dar [29]. Alternativ zu Methotrexat kommen MycophenolatMofetil oder Sirolimus zum Einsatz.…”

STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity

“…Antigen presenting cells (APCs), derived from both donor and host, play important roles in the development of acute GVHD by producing pro-inflammatory cytokines, such as TNF-alpha (TNF-α) and IL-6, as well as by directly stimulating donor T cells 3–9 . The complex role of dendritic cells (DCs), a potent subset of APCs, in GVHD pathogenesis is being increasingly appreciated 9 . But the effect of macrophages (MFs), another type of APC which infiltrate GVHD target organs 10, 11 on GVHD is less well-understood.…”