Cellular Modulation Of Gvhd And The Separation Of Gvhd From

Experimental and clinical experience have suggested that host cells surviving the transplant conditioning regimen may be instrumental in the regulation of GVHD.58-61 The availability of sensitive methods for detecting the presence of residual host cells (e.g., microsatellite analyses evaluating variable number of tandem repeat sequences) has demonstrated that at least a transient presence of host cells in many patients can be seen following HSCT.6263 An increased incidence of acute GVHD with increasing intensity of the preparative regimen, possibly because of the increased cytokine release and damage to host elements following these aggressive preparative regimens, has been observed.64 A relationship between the presence of mixed lymphohematopoietic chimerism and a reduced incidence of acute GVHD has also been seen in some series.65-67

In several animal models the intentional induction of mixed lymphohematopoietic chimerism has been associated with a reduction in the incidence of GVHD.40'60'68'69 These mixed chimeric states are achievable following either myeloablative preparative regimens in which a combination of mixed T-cell-depleted syngeneic and T-cell-depleted allogeneic marrow is transplanted ("mixed" marrow transplantation) or following nonablative preparative regimens with peri-transplant in vivo anti-T-cell therapy.58687071

Clinical trials at the Massachusetts General Hospital have been conducted utilizing similar nonmyeloabla-tive preparative regimens for the induction of mixed chimerism followed by DLI in patients with advanced hematologic malignancies.72-74 Mixed chimerism has been reliably achieved with regimens consisting of cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. Sustained remissions of chemore-fractory lymphoproliferative malignancies have been observed in a number of patients who achieved mixed chimerism followed by either spontaneous conversion to full donor hematopoiesis or DLI, which resulted in chimerism conversion. In several cases this chimerism conversion following DLI was not accompanied by significant clinical GVHD, providing proof of principal that GVHD is separable from GVM in mixed chimeras given delayed DLI. Sustained mixed lymphohe-matopoietic chimerism was also shown to be achievable following haploidentical stem cell transplanta-tion.72 An increased risk of GVHD in recipients of haploidentical transplants has, however, prompted a revision of the strategy in an effort to induce a GVH free state of mixed chimerism as a platform for DLI. A combination of vigorous in vivo T-cell depletion with an anti-CD2 monoclonal antibody and ex vivo T-cell depletion (using a CD34+ cell selection device) has resulted in the uniform induction of mixed chimerism following haploidentical stem cell transplantation with minimal or no GVHD. The conversion of chimerism, in some cases following delayed DLI, and in some cases with minimal or no GVHD, has provided further evidence that GVHD and GVM are separable, even in the haploidentical transplant setting.

Other cellular modulatory approaches to separate clinical GVHD from GVHD have included the administration of exogenous cytokines posttransplant to dissociate T-cell subset effector function75-77 (Table 98.3). Early clinical trials have not substantiated a benefit of high-dose IL-2 posthaploidentical stem cell transplan-tation.78 However, the optimal timing and dosing of IL-2 may not have been achievable clinically.

Table 98.3 Separation of GVHD from GVT Method Mechanism

■ Initial bidirectional tolerance Induction of mixed ■ Resolution of pro-inflammatory lymphohematopoietic cytokine milieu prior to DLI

chimerism, delayed DLI ■ Confinement of the GVL

alloresponse to the lymphohematopoietic space

Ex vivo T-cell subset GVHD protection from

(CD8+ cell) depletion CD8+ cell removal, preservation of GVT effect from CD4+ cells, other effector cell populations

Enrichment Inhibition of GVHD by for CD4+, CD25+ cells T-regulatory cells

ATG/TLI conditioning Increase of regulatory natural killer T cells

Depletion of Inhibition of The capacity of

L-selectin+ T cells T cells to home to lymph nodes

DLI, donor lymphocyte infusion; GVL, graft-versus-leukemia; GVHD, graft-versus-host disease.

Manipulation of the cellular environment of the graft may also contribute to a separation of GVHD and GVM. As discussed above, CD8+ T-cell-depleted marrow grafts may be associated with less GVHD and preservation of potent GVL effect,49 and CD8+ T-cell-depleted DLI have been shown to induce remissions in patients with hematologic malignancies in relapse after allogeneic stem cell transplantation, with less GVHD than occurs with unmanipulated DLI (with comparable numbers of CD4+ cells).79

On the basis of preclinical murine models showing that NK1.1+ TCR ap+ cells have non-major histocompatibility complex (MHC)-restricted natural suppressor activity and the percentage of these cells can be increased by the administration of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG), clinical trials utilizing TLI/ATG have been initiated by Strober and colleagues in an effort to suppress GVHD and preserve a GVL effect.80 A comparable human CD8+ NK+ cell population of natural suppressor cells has been shown to be increased in percentage following TLI/ATG conditioning. Impressive GVHD protection and disease-free survival probabilities have been demonstrated in early clinical trials of reduced-intensity of transplantation for advanced hematologic malignancies.81

Given the complexity of the cellular and cytokine interactions that affect the incidence and severity of GVHD, an only preliminary understanding of how the host—donor cellular environment might be manipulated to prevent GVHD exists. Which host or donor regulatory cells are important in the suppression of GVHD, for example, remain to be determined. Several cell populations including the NK1.1+ murine cell population and the CD4+ CD25+ cell subset and lym-phokine-activated killer cells exhibiting both veto and natural suppressor activity have been postulated as having a regulatory role in the suppression of the GVH reaction.82 83 Given the compelling experimental and clinical evidence for a protective effect of cytokines and regulatory cell populations, future efforts should be made to define the mechanism of these effects and hopefully optimize their clinical benefits.

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