The manuscript published by Vianna et al1 presents the results of using rabbit-derived antithymocyte globulin (rATG)+Rituximab as induction therapy, in a larger cohort than previous reports. They present the incidence and severity of acute cellular rejection (ACR) compared with other induction protocols previously used in the same program. The novelty of the approach and the format of the manuscript give rise to different commentaries.
In complex procedures, like all different types of transplants involving the intestine, it has been almost standard for large volume programs to group or stratify patients and report long-term results based on the type of induction therapy used.1-3 This methodology used for analysis seems to ignore that, most probably, the longest term graft and recipient outcome will be associated to all changes occurring over time (based on each individual clinical behavior) together with the therapeutic changes made as a result of the evolving knowledge in the different aspects of the multidisciplinary care required for each patient, rather than in the induction therapy elected.
Over the years, we have also observed that each era seems to be better than the previous one. However, each period has clear cutoffs for immunosuppressive strategies, rather than a thoughtful transition process or a final “take home” message, determining at least, as a result of the experience, on which group of patients the proposed protocol should or should not be applied. It also seems that each era has served to improve early outcomes, but rates of graft loss beyond 1 year have not improved as expected yet.4
In the article of Vianna et al,1 the authors present a larger cohort of patients treated with a novel and combined immunosuppressive induction, which offers the benefit of a using anti-T and B-lymphocytes therapy.
It has been shown that rATG contains antibodies against plasma cell/B cell antigens as well as the expected T cell antigens. In addition to the T and B cell depletion, studies have shown a possible protective effect of rATG against reperfusion injury when it is administered before reperfusion of solid organs; however, by adding a chimeric anti-CD20 monoclonal antibody, the approach will more efficiently remove B cells, with fewer side effects, while adding the potential benefit of a possible reduction in the incidence of PLTD.
This approach could be considered as one of the most thoughtful and “intestinal transplant oriented” because the intestine has the highest lymphocyte load of any organ,5 while the implications of preformed or de novo donor specific antibodies bring to the field significant innovations, from pretransplant immune modulation to posttransplant monitoring and treatment6,7 as well as the novel concept that, although inclusion of the liver as part of the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect is lost among recipients with persistent of de novo donor specific antibodies.7,8
Moreover, it has been shown that B cells that recover are significantly depleted of memory CD27+ B cells for as long as 2 years after a single dose1; in this line of reasoning, a benefit in antibody-mediated rejection could have been expected, but intriguingly, there was no different incidence in chronic rejection under the different induction protocols used. This may be due to the aforementioned weaning influence of the induction therapy in the long-term posttransplant, where chronic rejection rises, or simply because the follow-up time of the cohort was not long enough to detect differences. It will be interesting to attend to the follow-up comparison of this cohort in a few years.
On the other hand, differences were observed in ACR incidence depending on the use of the combined induction therapy; therefore, we could wonder if there is any role for B cells in ACR, either as antigen-presenting cell or as standard player, that can be prevented by rituximab treatment.1
The novel proposed protocol shows that it will not only be able to provide a high ACR-free survival but also a severe ACR-free survival benefit; furthermore, it also has a reduced rate of posttransplant infections, favoring therefore long-term graft and patient survival. Although the majority of long-term ACR-free/severe ACR-free survivors belong mainly to modified multivisceral transplant and multivisceral transplant and mostly to the group of patients treated with rATG/Rituximab, Figure 2D shows the benefit of the proposed therapy in isolated grafts as well.
The manuscript also reports that in the short term, results of the proposed therapy and Alemtuzumab seem comparable. But the fact of observing a higher infections related complication in the Alemtuzumab group will not favor its use.
Induction therapies impact on early and might condition middle-term outcomes.
Authors support this statement by showing a reduction on the initial incidence of ACR (and its types) at a maximum of 24 days; however, as it was stated in our first paragraphs, the long-term results seem to be resultant of the impact of the maintenance immunosuppressive protocol used as well as the changes made according to the clinical outcome of a given patient.
Authors have a great opportunity in the close future to further evaluate if there is any difference in the frequency of circulating CD4+ CD45RA− Foxp3 memory Treg between groups to learn the immunological impact and to better define which patient might benefit from receiving this novel approach, like it was proposed by Ceulemans et al,9 because although such a role has been described for rATG, there is no evidence for Rituximab or their combination.
As additions: this observational study differs from other manuscripts from single centers and the International Registry6,10 in terms of the long-term benefit of using mammalian targets of rapamycin as maintenance immunosuppressive regime, and finally, it also adds an adequate statistical analyses on other technical innovation proposed to perform stoma-free procedures. Here, it was seen that there is no higher incidence of ACR in patients with ostomy built; and although it is not a primary end-point, there is a recommendation that the decision of not doing it will only be supported by the patients’ or centers’ wish of improving quality of life but it should be done under a careful clinical monitoring and probably would have the best of benefit in MTV cases.
This manuscript together with the reduced number of intestinal procedures performed worldwide should inspire us to consider using such protocol as part of a prospective, multicenter study to obtain the quality of evidence required to continue improving not only early but also long-term results in intestinal transplantation.
1. Vianna RM, Mangus RS, Fridell JA, et al. Induction immunosuppression with thymoglobulin and rituximab in intestinal and multivisceral transplantation. Transplantation. 2008; 85:1290–1293
2. Abu-Elmagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann Surg. 2009; 250:567–581
3. Abu-Elmagd KM, Costa G, Bond GJ, et al. A decade of experience with a single dose of rabbit antithymocyte globulin or alemtuzumab pretreatment for intestinal and multivisceral transplantation. Clin Transpl. 2012155–166
4. Selvaggi G, Nishida S, Levi D, et al. Intestinal and multivisceral transplantation at the University of Miami. Clin Transpl. 2009211–217
5. Grant D, Abu-Elmagd K, Mazariegos G, et al.; Intestinal Transplant Association. Intestinal transplant registry report: global activity and trends. Am J Transplant. 2015; 15:210–219
6. Meier D, Cagnola H, Ramisch D, et al. Analysis of immune cells draining from the abdominal cavity as a novel tool to study intestinal transplant immunobiology. Clin Exp Immunol. 2010; 162:138–145
7. Gondolesi G, Blondeau B, Maurette R, et al. Pretransplant immunomodulation of highly sensitized small bowel transplant candidates with intravenous immune globulin. Transplantation. 2006; 81:1743–1746
8. Cheng EY, Everly MJ, Kaneku H, et al. Prevalence and clinical impact of donor-specific alloantibody among intestinal transplant recipients. Transplantation. 2017; 101:873–882
9. Ceulemans LJ, Braza F, Monbaliu D, et al. The Leuven Immunomodulatory Protocol promotes T-regulatory cells and substantially prolongs survival after first intestinal transplantation. Am J Transplant. 2016; 16:2973–2985
10. Fishbein TM, Florman S, Gondolesi G, et al. Intestinal transplantation before and after the introduction of sirolimus. Transplantation. 2002; 73:1538–1542