11.1. Allogeneic HSCT
Several factors have been limiting for autologous transplants. First, regimens have been less than maximally intensive and thus have not achieved eradication of immunologic memory. Second, reinfusion of potentially pathogenic T and B cells is a potential cause of relapse. The latter has been thought to justify allogeneic transplantation, with its attendant higher risks (10-30% mortality), mainly relating to graft versus host disease (GVHD). Several case reports and series support this notion. A child with autoimmune hemolytic anemia that was refractory to immunosuppression and splenectomy had only a 7-week remission after autologous transplantation, but was still in remission 18 months after an HLA-identical unrelated donor transplant (De Stefano et al., 1999). A graft-versus-autoimmunity effect has been proposed in a patient given an allogeneic stem cell transplant for chronic myeloid leukemia, who also had severe psoriasis (Slavin et al., 2000). This is also compatible with long-term control of RA in a small number of allografted patients. These patients had received conditioning regimens very similar to that given in trials of autografting in RA (i.e., Cy 200 mg/kg), and the longer remission in the allografted patients suggest that the type of graft rather than the conditioning regimen determined outcome. However, both long-term remissions with autologous HSCT and relapses following allo-geneic HSCT (with full donor chimerism) have been observed in AD after transplant, as well as in newly occurring AD (Rouquette-Gally et al., 1987, 1988; Snowden and Heaton, 1997; Baron et al., 1998).
Novel concepts with nonmyeloablative conditioning regimens may reduce early transplant-related mortality to less than 10%, making allogeneic HSCT for AD more acceptable. Still, the risk of GVHD will remain (Binks et al., 2001), and it is unclear whether the target for HSCT in AD can be defined as clearly as in malignant and inherited disorders. Carefully selected cases with early but high risk disease and low risk for transplant-related mortality (young age, HLA-identical siblings) should provide an answer. For these reasons, allogeneic HSCT for the treatment of severe AD must await further refinement of the transplant procedure and, in particular, the prevention of GVHD. The international guidelines stipulated that autologous HSCT should be the preferred approach (Gratwohl and Tyndall, 1997). So far, this has been mostly adhered to with allo-geneic HSCT for AD alone having been performed mainly in refractory cytope-nias (Gratwohl et al., 2001).
Despite new developments, arguments not to use allogeneic HSCT in the first instance remain the same. Treatment-related toxicity is high, GVHD cannot yet be avoided and might interfere with the preexisting disease without the potential additional benefit of "graft-versus-autoimmunity." Unlike malignancy, there is no definable clone of autoaggressive cells to be eradicated. Furthermore, incomplete or slowed immune reconstitution after allogeneic HSCT might lead to late development of a donor-type AD, even more so in predisposed patients.
It remains open to debate whether reduced intensity conditioning regimens might alter these perspectives, since they have been shown to reduce early mortality. So far, they have not reduced risk of GVHD and long-term follow-up is required. Still, there is a consensus that it might be appropriate under carefully selected conditions to begin the planning of phase I/II studies to evaluate the role of allogeneic HSCT. Conditioning with Cy ± ATG as used for aplastic anemia for many years might be the most appropriate choice.
In general, immune reconstitution must be considered separately for autol-ogous and allogeneic transplantation. According to the many variations of each procedure (see also Table 24.4), the impact of individual regimens on immune reconstitution may differ, even before considering the effect of different diseases and age groups. Among the possible measures for immune reconstitution are cell surface markers to determine the appearance and development of different cell lines, the response to infectious agents and vaccination, and the repertoire of adaptive immunity to non-self and self-antigens. In the autologous setting, the method used for mobilization, the extent of the immunoablative regimen, and negative and positive selection of the autograft may influence reconstitution of the hemopoietic and immune systems. In children, CD4+CD45RO+ peripheral T cell expansion occurred within 16 days after transplant. Natural killer (NK) cell (CD16+/CD56+) counts normalized rapidly. After day 30 an inverted CD4/CD8 ratio was still present, and T cell (CD3+, CD3+CD4+, CD4+CD45RA+) recovery was delayed until 24 months after the autograft (Kalwak et al., 2002). In adults, lymphocyte subset recovery and T cell receptor (TCR) beta-chain variable region did not differ between patients receiving unmanipulated or CD34-selected autol-ogous HSCT (Peggs et al., 2003). A study of dendritic cell (DC) subset reconstitution after autologous HSCT involving 58 patients showed that peripheral blood CD11c+CD123low type 1 DC (DC1) and CD11c-CD123+ type 2 DC (DC2) counts reached preconditioning levels 20 days after unmanipulated autologous HSCT. When CD34 selection was performed, recovery to levels after mobilization was delayed until day 60. Levels of DC1 and DC2 approached normal from day 180 in the group receiving unmanipulated grafts, while in those receiving CD34-selected HSCT, DC1 and DC2 counts remained persistently lower than normal (Damiani et al., 2002).
The reconstitution of the immune system after allogeneic HSCT is complex, and may be significantly impaired by chronic GVHD. After allogeneic HSCT with full donor chimerism, recovery of TCR rearrangement diversity is more rapid in younger individuals. Recovery in older patients was slower, but little difference remained at 9 months. In this series, low levels of TCR rearrangement correlated with severe opportunistic infections and with GVHD (Lewin et al, 2002). The re constitution of recipient NK cell repertoire after HLA-matched HSCT followed the killer immunoglobulin-like receptor (KIR) pattern of the donor in the majority of cases, whereas in the others no uniform pattern was evident, and severe clinical complications occurred (Shilling et al., 2003). DC recovery after allo-HSCT was rapid, DC1 exceeding DC2 (Chklovskaia et al., 2004), in contrast to the levels after autologous HSCT (Damiani et al., 2002). NK cell reconstitution was also rapid, with a high proportion of interferon-gamma-producing CD56highCD16-/low NK cells and reduced CD56lowCD16high cells (Chklovskaia et al., 2004). This differs from the data for autologous HSCT (Damiani et al., 2002).
The finding of T cell receptor excision circles (TRECs) in T cells recently exiting the thymus (Douek et al., 2000) has allowed a more detailed analysis of normal and autoaggressive T cell reactions following HSCT for AD. Following HSCT for AD, some adult patients have shown an increase in the number of lymphocytes bearing TRECs, indicating that the thymus may become reactivated and theoretically capable of inducing central tolerance.
Recipients of autologous HSCT with CD34 selection had higher rates of infection with agents other than cytomegalovirus (CMV) than those of unse-lected autografts. The principal cause of the difference were varicella zoster virus, parainfluenza virus 3, and bacterial infections (Crippa et al., 2002). Fungal infections showed no significant differences between CD34-selected and -non-selected recipients (Crippa et al., 2002). Donor T cell immunity against CMV, as measured by HLA-A2 tetrameric complexes targeting viral phospho-protein UL83, was established in most recipients unless prolonged immunosuppression was required for GVHD (Aubert et al., 2001). CMV infection was associated with higher CD8+ counts and decreased TCR beta-chain variable region diversity (Peggs et al., 2003).
Patients treated with allogeneic HSCT have a higher rate of infections compared with those receiving autologous HSCT (Einsele et al., 2003). EBV activation after allogeneic HSCT was associated with low CD8+ levels, and a high cellular viral load preceded reactivation (Clave et al., 2004). The rate of severe infections after allogeneic HSCT appears to depend on the source of the graft, since it was significantly higher in marrow recipients than in patients receiving filgrastim-mobilized peripheral blood stem cell grafts (Storek et al., 2001).
HSCs resist the cytotoxic effects of cyclophosphamide, and therefore theoretically, an HSCT is not needed following aplasia induction and G-CSF-supported reconstitution. Such a strategy has been successfully employed in aplastic anemia and applied to SLE (Petri et al., 2003). Early results are encour aging, but a significant number of patients had not had conventional pulse cyclophosphamide therapy and the reconstitution times, especially for platelets, were prolonged compared to rescue with HSCT. Both procedures remain research-based rather than standard therapy.
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