Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution

Abstract

Graft-versus-host disease (GVHD), a major complication after allogeneic transplantation, can be abrogated by the Campath (anti-CD52) monoclonal antibody. The induction of acute GVHD requires host antigens to be presented to donor T cells by antigen-presenting cells (APCs). Recent evidence has suggested that only host APCs can interact with donor T cells in the induction of GVHD. Because CD52 has been reported to be expressed on DCs, we reasoned that pretransplant Campath-1G might have a direct effect on circulating DCs in addition to any effects on donor T cells. Using direct immunostaining, we demonstrated expression of CD52 on DCs and that Campath-1G killed purified DCs in vitro. In vivo Campath also depleted DCs. Twenty-four hours after the first dose of Campath-1G, circulating DCs were reduced by a mean of 79% (range, 44%-96%). By day 0 after 5 doses of Campath-1G and chemoradiotherapy conditioning, DCs became undetectable in 7 of 9 cases, whereas in 6 of 7 patients receiving conditioning therapy without Campath-1G, host DCs were still detectable. The reconstitution of circulating DCs after transplantation was not affected by Campath-1G and in both groups DC1 (CD11c ؉ ) recovered more rapidly than DC2 (CD11c ؊ ). Analysis of chimerism confirmed that the DCs recovering after transplantation in patients receiving Campath-1G were of donor origin. We conclude that in vivo Campath-1G causes a rapid depletion of host circulating DCs and that this may, in part, explain the low incidence of acute GVHD. The reconstitution of donor DCs was not delayed, which may be important in preserving immune reconstitution. IntroductionHigh-dose chemoradiotherapy followed by the allogeneic transplantation of hematopoietic stem cells from either bone marrow (BM) or peripheral blood stem cells (PBSCs) is widely used in the treatment of malignant and nonmalignant hematologic diseases. However, allogeneic transplantation is frequently associated with the development of acute graft-versus-host disease (GVHD), which is thought to occur as a result of donor T-cell activation damaging host tissues particularly affecting the liver, skin, and gastrointestinal tract. 1,2 Current therapeutic approaches to the prevention of acute GVHD after transplantation include immunosuppression with agents such as cyclosporin and methotrexate. However, despite these measures GVHD still remains a significant cause of morbidity and mortality. [3][4][5] Alternative strategies for the prevention of acute GVHD have focused on the depletion of donor T cells from the graft before infusion into the host. [6][7][8] Although it has been recognized for many years that T-cell depletion decreases the risk of GVHD development, 6,9 it also increases the risk of leukemia relapse in chronic myeloid leukemia 10 and graft rejection. 11 A number of different approaches to T-cell depletion have been used including CD34 ϩ cell selection 12,13 and ex vivo treatment of the graft with monoclonal antibodies. For this purpose, Campath-1M, which recognizes the CD52 antigen, has been...

Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step

“…It is also known to deplete circulating DC and DC precursors (unlike ATG). 19 Finally, in addition to the conditioning regimen employed, GVHD prophylaxis may be a significant variable. Most patients described in the series above received standard MTX and CYA for GVHD prophylaxis.…”

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease

“…( Figure 5) Discussion RIT preparative regimens differ greatly in the intensity of the preparative regimen, the types of the immune suppression utilized to prevent graft rejection, and the intensity and duration of the prophylaxis used to prevent serious aGVHD. 3,5,7,13,35,36 Many regimens result in mixed hematopoietic chimerism, requiring subsequent DLIs to establish full donor chimerism, maintain engraftment, and augment the GVM effect. 7,[37][38][39][40] Despite decreased regimen-related toxicities and NRM with these regimens, the incidence of serious grade II-IV aGVHD, in non-T-cell-depleted HSCTs, remains at 25-50%.…”

“…A similar mechanism has been proposed to explain the decreased incidence and severity of aGVHD reported in patients who received Campath-1G as part of a preparative regimen. 35 The use of infusional pentostatin in this regimen was to induce immune suppression and therefore facilitate engraftment. 53 Pentostatin is a potent inhibitor of the enzyme adenosine deaminase, and its mechanism of cytotoxicity differs from the other purine analogs.…”

State-of-the-art acute and chronic GVHD treatment

“…Early donor dendritic cell reconstitution has been associated with decreased incidence of severe GVHD [67,68]. From day 100 onwards after allogeneic HSCT the persistence of host dendritic cells correlates with onset of severe aGVHD and cGHVD [69,70].…”