Overview of T-cell depletion in haploidentical stem cell transplantation.

Abstract

Graft-versus-host disease (GvHD) is a common complication of allogeneic stem cell transplantation in which functional immune cells in the transplanted graft recognise the recipient as “foreign” and mount an immunological attack. Clinically, GvHD is divided into acute and chronic forms. The acute form of the disease is normally observed within the first 100 days after transplantation1. The chronic form of GvHD normally occurs after 100 days2. However, this arbitrary distinction based on the time of onset fails to reflect the different pathophysiological mechanisms and clinical manifestations of acute and chronic GvHD. Acute GvHD can occur after day 100 in patients who received a non-myeloablative conditioning regimen or donor lymphocyte infusions. In addition, GvHD with typical clinical features of chronic GvHD can develop well before day 100 and concurrent with acute GvHD3. The National Institutes of Health consensus development project has, therefore, defined new criteria for the diagnosis, staging, and response assessment of chronic GvHD. The current consensus recommends that acute and chronic GvHD should be distinguished by clinical manifestations and not by time after transplantation. The consensus conference recognises two main categories of GvHD, each with two subcategories. The broad category of acute GvHD includes classic acute GvHD (maculopapular erythematous rash, gastrointestinal symptoms, or cholestatic hepatitis), occurring within 100 days after hematopoietic stem cell transplantation or donor leucocyte infusion. The broad category of acute GvHD also includes persistent, recurrent or late-onset acute GvHD, occurring more than 100 days after transplantation or donor leucocyte infusion; for brevity, this subcategory is henceforth designated as “late acute” GvHD. The presence of GvHD without diagnostic or distinctive chronic GvHD manifestations defines the broad category of acute GvHD. The broad category of chronic GvHD includes classic chronic GvHD, presenting with manifestations that can be ascribed only to chronic GvHD. The broad category of chronic GvHD also includes an overlap syndrome, which has diagnostic or distinctive chronic GvHD manifestations together with features typical of acute GvHD4. Donor T-cells play a fundamental role in the immunological attack on host tissues in both acute and chronic GvHD. While the cytokine production pattern of acute GvHD is mostly TH1 type, TH2 cytokines predominate in chronic GvHD5. In particular, acute GvHD is mediated by donor lymphocytes infused into the recipient, in whom they encounter tissues profoundly damaged tissues by the effects of the underlying disease, prior infections, and the transplant conditioning regimen. The allogeneic donor cells encounter a foreign environment that has been altered to promote the activation and proliferation of inflammatory cells. Thus, acute GvHD reflects an exaggerated response of the normal inflammatory mechanisms that involve donor T-cells and multiple innate and adaptive cells and mediators. Three sequential phases can be conceptualised to illustrate the complex cellular interactions and inflammatory cascades that ultimately evolve into acute GvHD: (i) activation of antigen-presenting cells; (ii) donor T-cell activation, proliferation, differentiation and migration; and (iii) target tissue destruction6. Understanding of the pathophysiology of chronic GvHD is not so advanced as that of acute GvHD. Alloreactive T-cells have been implicated in the pathogenesis; however, the precise roles of specific T-cell subsets, autoantigens, alloantigens, and B-cells, and interactions of chemokines and cytokines have not been fully elucidated. The clinical manifestations of chronic GvHD are often similar to an autoimmune process, suggesting similar pathophysiology7,8. Patients with GvHD can manifest sclerodermatous skin changes, keratoconjunctivitis, sicca syndrome, lichenoid oral mucosal lesions, oesophageal and vaginal strictures, liver disease and respiratory failure9–11. Removal of T-cells from the donor graft (T-cell depletion) offers the possibility of preventing GvHD and, thereby, reducing transplant-related morbidity and mortality. The probability of acute GvHD ≥grade 2 after HLA-identical stem cell transplantation varied from 25–60% for patients transplanted with unmanipulated grafts and from 0–35% after T-cell-depleted stem cell transplants. Approximately 30–50% of patients develop chronic GvHD after an HLA-identical sibling stem cell transplant. The incidence of chronic GvHD may be even higher after allogeneic transplantation using unmanipulated peripheral blood stem cells because of the higher number of T-cells in these grafts. Extensive chronic GvHD requires prolonged immunosuppressive treatment and is associated with a mortality of more than 50%: most of the deaths are secondary to infections resulting from severe immune dysfunction12–14. T-cell depletion reduces the risk of GvHD in patients with either HLA-matched or partially matched donors and also allows the transplantation of haploidentical stem cells without increased incidence of GvHD15. Haploidentical stem cell transplantation is a valid approach for patients at high risk of disease progression without HLA-matched donors. In a haploidentical setting, most donors will share only one HLA haplotype with the patients. These haploidentical donors are readily available within a few days, are highly motivated to donate large numbers of stem cells (parental donors) and, with respect to further adoptive cellular therapy, are available during the post-transplant course16. A number of attempts to use haploidentical T-cell-replete unmanipulated bone marrow and myeloablative conditioning were made in the past. It should be highlighted that these attempts were associated with early severe and often fatal side-effects, including multi-organ failure and pulmonary oedema, a clinical picture resembling hyperacute GvHD17. While initial attempts at haploidentical stem cell transplantation used bone marrow as the source of stem cells, the possibility of mobilising and collecting peripheral stem cells and the development of graft-engineering methods for peripheral blood stem cells has allowed the design of strategies to overcome some of the obstacles of haploidentical transplantation, such as engraftment failure and the high incidence of GvHD18. A major advantage for patients transplanted with T-cell-depleted grafts is a better quality of life because of the less morbidity caused by acute and chronic GvHD. The lower probability of transplant-related morbidity and mortality offers a larger number of patients the possibility of becoming eligible for various forms of additional immunotherapy such as donor leucocyte infusions with disease-specific cytotoxic T-lymphocytes, activated donor natural killer cells and dendritic cell vaccination strategies. An increase of the graft-versus leukemia effect without introducing significant GvHD may result in lower relapse rates and increased probabilities of leukemia-free and overall survival19–21.