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Graft-Versus-Host Disease
 - Cell Therapy Approaches

Allogeneic solid organ and bone marrow transplantations are well-established treatments for end-stage failure of several major organs and a variety of hematological malignancies, autoimmune diseases, inherited metabolic disorders, histiocytic disorders, and malignant solid tumors. Graft versus host disease (GvHD) is a devastating and life-threatening immunological complication of transplantation. 25–35 % of hematopoietic stem cell transplantation (HCT) recipients and 50% of organ transplantation recipients develop GvHD. GvHD is caused by disturbances in pathways of immunological reconstitution and failure to acquire immunological tolerance, thereby resulting in both alloimmune and autoimmune attacks on multiple host tissues. GvHD is classified as either acute or chronic, based on the degree of organ involvement, laboratory data, or histopathological findings. It is initiated by alloreactive donor T cells which recognize host minor and major histocompatibility (MHC) antigens or recipient antigen-presenting cells (APC) presenting donor MHC alloantigens in the context of self-MHC, and then proliferate, and damage target tissues. Currently, GvHD is avoided by a combination of immunosuppressive drugs and biological agents such as cyclosporin A and anti-thymocyte globulin (ATG), respectively. Treatment varies according to organ and disciplines. Long-term patient and graft survival remain suboptimal due to the toxic side effects associated with long-term use of immunosuppressive drugs which exposes patients to infections. The standard treatment for GvHD is administration of glucocorticoids and additional immunosuppressive agents or steroid-sparing drugs, such as sirolimus; however, these strategies have had only limited success due to increased risk of infection and treatment-related mortality.

Thus, a major goal of transplantation research is to promote ‘tolerance’, a state in which the host's immune system can be reprogrammed and then guided to accept a transplant without the need for long-term immunosuppression. Another goal is to treat GvHD by stabilizing the immune system. In this pursuit, clinically applicable protocols have been developed in efforts to tip the immunological balance in favour of regulation by either the in-vivo expansion or the infusion of ex-vivo-expanded T cells with regulatory activity. Several potential treatments are being clinically evaluated, including antimetabolites, mTOR inhibitors, cytokine blockade, monoclonal antibodies and phototherapy.


Cell Therapy Approaches

Cellular therapies for GvHD include treatment with mesenchymal stem cells (MSCs), regulatory T cells (Treg), dendritic cells (DC) and natural killer T cells (NK):

T regulatory cells (Tregs): There are many different types of Tregs, all of which can be characterized by the expression of the FoxP3. Tregs are categorized as naturally occurring or inducible cells and are distinguished by the DNA methylation pattern of a specific region in the FoxP3 gene. Tregs have been demonstrated to suppress a variety of immune responses and have proven effective in preventing GvHD in murines. Tregs have a broad immunomodulatory effect, including an impact on CD4+ and CD8+ T cell functionality by cell–cell contact or a contact-independent route, which involves inhibitory cytokines that prevent differentiation, activation and proliferation, or effecting dendritic cells (DCs).

However, the major limitation impeding the clinical application of Treg-based therapy to prevent GvHD is the complexity of obtaining sufficient numbers of antigen-specific Tregs and maintaining their regulatory properties after infusion. To overcome this obstacle, expansion of highly purified Tregs (however, a Treg-specific cell surface marker is absent) or establishment of culture conditions that favour Treg cell growth is required.

Clinical trials using Treg cell therapy found it to be well tolerated and safe. In some cases, a trend toward reduced occurrence of GvHD was observed. Ex vivo-expanded CD4+CD25+CD127- Tregs used to treat chronic and acute GvHD, induced significant alleviation of the symptoms and reduction of pharmacologic immunosuppression in chronic GvHD patients, while only transiently improving the condition in cases of acute GvHD. Ex vivo-expanded CD4+CD25+FoxP3+ umbilical cord blood-derived Tregs administered to patients after umbilical cord blood transplantation, reduced incidence of severe acute GvHD. Patients with haematological malignancies received HCT with varying doses of donor Tregs, without ex-vivo expansion, and donor conventional T cells (Tcons), without any other adjuvant immunosuppression. Treatment prevented acute or chronic GvHD while favouring Tcon-mediated post-transplantation immune reconstitution.

Mesenchymal stem cells (MSCs) are heterogeneous plastic-adherent cells that can be isolated from many tissues and are capable of differentiating into various nonhematopoietic lineages. They also feature immunomudolatory characteristics, and are therefore considered candidates for treatment of GvHD, without the need for HLA-matching. Clinical trials have demonstrated that MSC infusions modulate inflammation and immune responses by secreting soluble mediators and probably do not contribute to organ regeneration. In children, there is evidence of MSCs engraftment. The clinical trials proved that the MSCs appeared to be safe, with no toxicity from its infusion (and in particular no report of pulmonary embolism). In the majority of trials MSC infusion improved patient status.

MSCs are also used to treat steroid-refractory GvHD and have some beneficial effects, albeit transient at times. No side-effects were seen after MSC infusions in this patient population. An inverse correlation was observed between the expansion of passages of MSCs prior to infusion and the clinical response to the treatment; low passages induced better response.

A number of trials are currently assessing MSC-based prophylactic treatment for GvHD. In clinical trials with patients that are treated for haematological malignancies MSC treatment induced a higher rate of tumor recurrence. MSC infusions have been suggested to have a positive impact on hematopoiesis after autologous HCT. Several studies evaluating allogeneic co-transplantation of MSCs and HCT, found it to be feasible and safe, suggesting reduced risk for graft failure. MSC donor chimerism was scarcely detected.

There is no conclusive data regarding the effect of MSCs on GvHD, primarily due to the vast variability in the protocols used: the source of the MSCs, the dose used and the specific GvHD condition treated.

Dendritic cells (DCs) are rare, heterogeneous bone marrow–derived professional APCs, which can stimulate innate and adaptive immunity and induce and maintain tolerance. DCs have been shown to inhibit GvHD in mice. Clinical studies have revealed an association between low total DC numbers at the time of engraftment and decreased patient survival, increased relapse, and increased GvHD. 

The use of donor natural killer (NK) cells for treatment of GvHD is being assessed in preclinical studies and they have been found to suppress GvHD . Clinical studies have demonstrated a correlation between NK cell doses in HCT to GvHD occurrence and severity, with lower incidence of GvHD in patients with high NK doses.

Graft-Versus-Host Disease