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Commentaries

On Poetry and Vascularized Composite Allografting

Platt, Jeffrey L. MD1; Kaufman, Christina L. PhD2; Cascalho, Marilia MD, PhD1

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doi: 10.1097/TP.0000000000003165
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The St. Otteran’s school in Waterford, Ireland underwent inspection in February 1926. A former student recalled the inspection as “just something to be got by” and did not recall the inspector.1 The inspector, a “sixty-year old smiling public man,”2 was the Minister of Education and Senator of the recently declared Irish Free State and privately the poet, W.B. Yeats. Yeats, the Senator, was much impressed by the students and the school and subsequently advised the Senate that novel approaches to education he observed should be broadly emulated.3 Yeats, the private man, drew broader conclusions that he put in a note, “School children and the thought that life will waste them...[because] life prepares for what never happens,”4 and in a poem, “Among School Children.2 Musing about differences between alloreactivity to kidney allografts and vascularized composite allografts (VCAs), Sicard et al5 arrived conclusions much like those of Yeats and present those conclusions in the current issue of Transplantation (in prose rather than in verse, as the Instructions for Authors provide no guidance about how to format verse). The pertinent conclusions in Yeat’s poem are found in the final lines:

O chestnut tree, great rooted blossomer,

Are you the leaf, the blossom or the bole?

O body swayed to music, O brightening glance,

How can we know the dancer from the dance?2

Sicard et al5 are among few in the world who expertly manage both kidney transplants and VCA. Their impression that humoral reactivity and antibody-mediated-rejection (AMR) of such concern in kidney transplantation might occur less often and differently in VCA, is noteworthy, to say the least. Sicard et al5 point out that diagnostic markers of AMR in kidney transplantation,—donor-specific anti-HLA antibodies (DSAs) in blood and deposits of C4d and vascular inflammation in biopsies—are sometimes absent when AMR is present and sometimes present when AMR is absent. This observation might recall Yeats’s chestnut tree, being not trunk, nor limb, nor blossom alone but all of these and more.6 But, the DSA, C4d, and inflammation that help diagnose rejection, are not rejection or even necessarily part of rejection. Rejection effaces graft function and injures or destroys the graft; DSA in blood and C4d and inflammation associated with viable, functioning vessels do none of these (inflammation can trigger thrombosis and ischemia, but not invariably and development requires blood vessel function). Instead, alloantibodies (in blood) and C4d and inflammation in grafts might prevent or heal injury (as discussed below and in our reviews).7-9

During the life of a graft, the antibodies that cause rejection bind to the graft. Antibodies in the circulation (DSA) however either fail to compete for binding or await the synthesis of new antigen or removal of bound antibodies. Of course, pathogenic antibodies can circulate before transplantation and after the vascular system of the graft is destroyed or the graft is removed. C4d marks sites where C4 reacted but, as a noncatalytic end product of C4 cleavage, it too plays no role in rejection and may even protect grafts by occupying sites otherwise available for reaction with C3b or C4b. Even vascular inflammation, though potentially part of a destructive process, also potentially limits the impact of immunity and triggers accommodation and regeneration, as work in cancer biology affirms.10

Given the profound differences between the structure and physiology of kidneys and the various tissues comprising VCA, one might expect that rejection of kidneys would be associated with different markers than the rejection of VCA. But, Sicard et al5 express particular interest in humoral alloreactivity, which should be associated with rejection of both types of grafts. Yet, after clinical VCA transplantation alloantibodies are uncommon and AMR is rare. Why?

We may lack the markers that would identify AMR in clinical VCA. But if that were so, either we would observe a high frequency of irreversible rejection or the outcome of untreated AMR would be markedly better for VCA than for kidney grafts. It is possible accommodation sustains VCA despite alloreactivity and alloantibodies. Sicard et al5 apparently consider this possibility by mention of the differential susceptibility of various organ transplants to humoral alloreactivity. However, Sicard et al5 also point out that VCA can undergo AMR if the recipient is presensitized. Hence resistance is neither absolute nor the singular explanation.

That returns us to the question why DSA are infrequent after VCA. Skin is a substantial component of nearly all VCA, and skin allografts have always been considered highly evocative of alloimmunity and alloantibodies. Many H-2 alleles and inbred lines of mice were identified using skin allografts, and skin allografts often evoke specific alloantibodies. This experience might predict VCA would elicit high levels of alloantibodies in nearly all recipients. Why does the prediction fail? VCA recipients are treated with immunosuppressive agents, but so are kidney transplant recipients. Are the agents more effective in recipients of VCA? Nor does the size of the graft or the components VCA transfer explain the differing manifestations of alloimmunity or infrequency of alloantibodies, as face allografts are much smaller than limb allografts and contain different sets of components.

Rather, we think that VCA grafting introduces a distinct and ongoing set of interactions, possibly reversible interactions, between the graft and the recipient.7,9 It was our view of this interaction that brought to mind Yeats’s dancer and dance (as pas de deux and not pas seul) as a working metaphor for examining the interactions (here we beg the indulgence of poets, dancers, and Professors of English and of French reading Transplantation for leisure). In the absence of immunosuppression, leukocytes and cellular particles from grafts migrate to lymphoid tissues through newly formed vascular and lymphatic vessels or connections that channel interactions between the recipient and graft. Both T cell and B cell responses ensue. But in the days to weeks that follow, T cell-mediated alloimmunity attacks and destroys the vascular bed disconnecting the graft and recipient before allogeneic B cell responses mature. Allogeneic B cell responses originate in germinal-center-reactions with repeated layers of somatic hypermutation and selection occurring over ~21 d. Once the reaction is complete, the graft has minimal interaction with activated B cells and plasma cells, which are free to produce abundant amounts of alloantibody (B cell responses detected earlier likely reflect either heightened production of natural antibodies or occult presensitization). VCA transplantation in immunosuppressed recipients triggers a profoundly different course of events. Under conditions of immunosuppression, T cell activation is delayed, allowing antigen, solubilized by actions of natural antibodies and/or complement on free-tissues to act in monomeric form on naive B cells to induce anergy or suppression (in the absence of immunosuppression, soluble antigen also reaches lymph nodes but activated T cells avert anergy). Where soluble antigen does not undermine B cell responses, solubilized antigen in the circulation hinders detection and effector actions of the alloantibody. Alloantibodies may still arrive in the graft, but do so slowly, allowing endothelial cells and other cells to adopt the physiology of accommodation, which together with mild inflammation promotes the uptake and processing of bound antibody and C4d.7

Whether and to what extent this “dance” distinguishes the outcomes of VCA from the outcomes of other transplants remains to be determined. But, probing this matter, like inspecting St. Otteran’s school, could deepen the perspective experience brings.

REFERENCES

1. Ryan SM. Gould W. The paddler’s heritage: Yeats’s visit to St. Otteran’s School, 1926. In: Yeats Annual No. 7. 1990207–208
2. Yeats WB. Finneran RJ. Among school children. In: The Collected Poems of W.B. Yeats. 1996Revised 2nd ed. Scribner Paperback Poetry editionNew York: Simon & Schuster; 544
3. Torchiana DT. Jeffares AN, Cross KGW. “Among school children” and the education of the Irish spirit. In: Excited Reverie. 1965:London: Palgrave Macmillan;
4. Corcoran NWB. Yeats’s “Among School Children”: the poem and its critics. Poetry and Responsibility. 2014:Liverpool: Liverpool University Press; 59–74
5. Sicard A, Kanitakis J, Dubois V, et al. Humoral alloreactivity in VCA recipients: should we learn from our experience? Transplantation[Epub ahead of print. February 7, 2020] doi: 10.1097/TP.0000000000003164
6. Hanson C. Yeats: Among school children. Critical Survey. 1973; 6:90–94
7. Platt JL, Kaufman CL, Garcia de Mattos Barbosa M, et al. Accommodation and related conditions in vascularized composite allografts. Curr Opin Organ Transplant. 2017; 22:470–476doi: 10.1097/MOT.0000000000000446.
8. Kaufman CL, Cascalho M, Ozyurekoglu T, et al. The role of B cell immunity in VCA graft rejection and acceptance. Hum Immunol. 2019; 80:385–392doi: 10.1016/j.humimm.2019.03.002.
9. Platt JL, Garcia de Mattos Barbosa M, Cascalho M. The five dimensions of B cell tolerance. Immunol Rev. 2019; 292:180–193doi: 10.1111/imr.12813.
10. Platt JL, Cascalho M. Cell fusion in malignancy: a cause or consequence? A provocateur or cure? Cells. 2019; 8:587doi: 10.3390/cells8060587.
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